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A Patient With CAD Deficiency Responsive to Uridine and Literature Review.

ABSTRACT: CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis, and pyrimidine can be alternatively recycled from uridine. Trio whole-exome sequencing identified CAD compound heterozygous mutations in a new male patient with global developmental delay (DD), refractory epilepsy, and anemia with anisopoikilocytosis. We further reviewed all published cases with CAD deficiency. Five patients were collected from two publications, including three males and two females, and all presented with DD, drug-resistant epilepsy, and anemia with anisopoikilocytosis. Four out of six patients (including the present case) were supplemented with uridine, which led to immediate cessation of seizures, resolved anemia with anisopoikilocytosis, and progress in global development. The other two patients, who were not treated with uridine, died at the ages of 4 and 5 years. In summary, CAD deficiency is probably a treatable neurometabolic disorder.

SUBMITTER: Zhou L

PROVIDER: S-EPMC7012989 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Patient With CAD Deficiency Responsive to Uridine and Literature Review.

Zhou Ling L Xu Han H Wang Tianshuang T Wu Ye Y

Frontiers in neurology 20200205

CAD encodes a multifunctional enzyme involved in <i>de novo</i> pyrimidine biosynthesis, and pyrimidine can be alternatively recycled from uridine. Trio whole-exome sequencing identified CAD compound heterozygous mutations in a new male patient with global developmental delay (DD), refractory epilepsy, and anemia with anisopoikilocytosis. We further reviewed all published cases with CAD deficiency. Five patients were collected from two publications, including three males and two females, and all ...[more]

PMID: 32117025

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Project description:IntroductionThe SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.MethodsWe involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.ResultsWe obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.DiscussionWe recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

Dataset Information

A Patient With CAD Deficiency Responsive to Uridine and Literature Review.

Publications

A Patient With CAD Deficiency Responsive to Uridine and Literature Review.

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