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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature.

ABSTRACT: Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare metabolic autosomal recessive urea cycle disorder. Only about 100 patients have been reported in the literature. As the population survives into reproductive years, pregnancy management becomes a new challenge for this clinicians. To our knowledge, there are less than three patients with successful pregnancies and deliveries found in the literature with no specific consensus on management or recommendations for HHH syndrome. We reviewed the current literature regarding pregnancy outcomes, combine it with our experience managing a patient through two successful pregnancies and identify a new concern of fetal intrauterine growth restriction. From this, recommendations for pregnancy management are made, including a detailed protocol for clinicians to use for disease management at delivery and in the post-partum period.

SUBMITTER: Ho B

PROVIDER: S-EPMC6498866 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature.

Ho Bernice B MacKenzie Jennifer J Walia Jagdeep J Geraghty Michael M Smith Graeme G Nedvidek Julie J Guerin Andrea A

JIMD reports 20190314 1

Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare metabolic autosomal recessive urea cycle disorder. Only about 100 patients have been reported in the literature. As the population survives into reproductive years, pregnancy management becomes a new challenge for this clinicians. To our knowledge, there are less than three patients with successful pregnancies and deliveries found in the literature with no specific consensus on management or recommendations for HHH syndr ...[more]

PMID: 31240152

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Project description:Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive disorder of the urea cycle. HHH has a panethnic distribution, with a major prevalence in Canada, Italy and Japan. Acute clinical signs include intermittent episodes of vomiting, confusion or coma and hepatitis-like attacks. Alternatively, patients show a chronic course with aversion for protein rich foods, developmental delay/intellectual disability, myoclonic seizures, ataxia and pyramidal dysfunction. HHH syndrome is caused by impaired ornithine transport across the inner mitochondrial membrane due to mutations in SLC25A15 gene, which encodes for the mitochondrial ornithine carrier ORC1. The diagnosis relies on clinical signs and the peculiar metabolic triad of hyperammonemia, hyperornithinemia, and urinary excretion of homocitrulline. HHH syndrome enters in the differential diagnosis with other inherited or acquired conditions presenting with hyperammonemia.A systematic review of publications reporting patients with HHH syndrome was performed.We retrospectively evaluated the clinical, biochemical and genetic profile of 111 HHH syndrome patients, 109 reported in 61 published articles, and two unpublished cases. Lethargy and coma are frequent at disease onset, whereas pyramidal dysfunction and cognitive/behavioural abnormalities represent the most common clinical features in late-onset cases or during the disease course. Two common mutations, F188del and R179* account respectively for about 30% and 15% of patients with the HHH syndrome. Interestingly, the majority of mutations are located in residues that have side chains protruding into the internal pore of ORC1, suggesting their possible interference with substrate translocation. Acute and chronic management consists in the control of hyperammonemia with protein-restricted diet supplemented with citrulline/arginine and ammonia scavengers. Prognosis of HHH syndrome is variable, ranging from a severe course with disabling manifestations to milder variants compatible with an almost normal life.This paper provides detailed information on the clinical, metabolic and genetic profiles of all HHH syndrome patients published to date. The clinical phenotype is extremely variable and its severity does not correlate with the genotype or with recorded ammonium/ornithine plasma levels. Early intervention allows almost normal life span but the prognosis is variable, suggesting the need for a better understanding of the still unsolved pathophysiology of the disease.

Project description:PURPOSE:There is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals. METHODS:We reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration. RESULTS:According to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged. CONCLUSION:Reconsideration of the application of the term "geographic atrophy" in the context of age-related macular degeneration seems to be prudent given ongoing advances in multimodal retinal imaging technology with identification of various phenotypic characteristics, and the observation of atrophy development in eyes under antiangiogenic therapy.

Dataset Information

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature.

Publications

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome in pregnancy: Considerations for management and review of the literature.

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