Clinical, Laboratory, and Short-Term Outcomes in Neonatal Nonketotic Hyperglycinemia

Background: Nonketotic hyperglycinemia (NKH) is a rare metabolism disorder with autosomal recessive transmission. Newborn infants characteristically present with hypotonia, lethargy, convulsions, and apnea and are generally lost within the first year of life. Objectives: The aim of this study was to evaluate the clinical characteristics, laboratory findings, and short-term results of infants diagnosed with NKH. Methods: The retrospective study included 10 infants diagnosed with NKH between August 2013 and July 2020. The clinical characteristics, laboratory findings, treatment methods, and short-term outcomes of the patients were evaluated. Results: The age range of patients (50% males vs. 50% females) was 2 - 8 days on presentation. The complaints on presentation were decreased breastfeeding, lethargy, convulsions, hiccups, apnea, and respiratory problems. In the physical examination, significant hypotonia and reduced or absence of newborn reflexes were predominant. Mechanical ventilation (MV) was required for nine patients. The cerebral spinal fluid/serum glycine ratio was > 0.08 in all patients, with median value of 0.19 (range: 0.12 - 0.30). The presence of a burst suppression pattern on electroencephalography and an increase in the glycine peak in magnetic resonance spectroscopy were the supportive diagnostic findings. Mutation analysis was performed on one patient. Seizures resistant to treatment were controlled with levetiracetam in three patients and dextromethorphan in one patient. Conclusions: According to the results, the most common clinical findings in NKH were severe hypotonia, seizure, and encephalopathy. In some cases, with resistant seizures, levetiracetam was found to be effective.

Novel GLDC Compound Heterozygous Variant Leading to Nonketotic Hyperglycinemia: Case Report and Literature Review

Nonketotic hyperglycinemia (NKH) is a lethal autosomal recessive disease resulting from alterations in glycine metabolism, commonly caused by mutations in glycine decarboxylase (GLDC). The symptoms of NKH usually manifest in the neonatal period, and can be categorized into severe NKH and attenuated NKH based on the clinical outcome. To date, only a few NKH cases have been reported in China. We here report a case of a neonate with severe NKH carrying a novel compound heterozygous variant in GLDC. The patient was a 68-h-old girl who had progressive lethargy, no crying, and poor sucking ability from birth, and was therefore transferred to our department. On admission, the patient was supported by intubation and ventilation and presented with profound coma. Metabolic investigation indicated a markedly increased glycine concentration both in the plasma and cerebrospinal fluid (CSF). Symptomatic treatments were administered, but the patient's condition did not improve substantially. Whole-exome sequencing identified compound heterozygous mutations (c.1261G>C, p.G421R and c.450 C>G, p.N150K) in GLDC, which were inherited from the mother and the father, respectively. The patient was hospitalized for 8 days in our department and died 2 days after discharge. We further summarize the clinical features, genetic characteristics, administered treatment, and prognosis of previously reported Chinese NKH patients for context. Our results highlight that due to the non-specific clinical phenotypes of NKH and difficulty in obtaining CSF samples, genetic testing is a crucial tool, not only for a diagnosis but also for predicting the clinical outcome and can potentially help to determine the optimal therapeutic strategy.

Homozygous Novel Variants in the Glycine Decarboxylase Gene Associated with Nonketotic Hyperglycinemia in a Distinct Population

Glycine encephalopathy (GE), also known as nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder due to a primary defect in the glycine cleavage enzyme system. It is characterized by elevated levels of glycine in the plasma and cerebrospinal fluid (CSF) and increased CSF to plasma glycine ratio.Mutations in three genes of the mitochondrial glycine cleavage system have been found to cause NKH. Most patients have a mutation in the GLDC.In this report, we present five new patients from Middle Eastern families with NKH. They were all born to consanguineous parents and two of them have family history of similarly affected sibling(s). All patients presented with neonatal encephalopathy associated with seizures. Their diagnoses were suspected clinically and confirmed biochemically.DNA sequence analysis of the five patients revealed five different pathogenic or likely pathogenic variants in the GLDC. Three were missense variants (c.2675C > T; p.Ala892Val), (c.2512A > G; p.Asn838Asp), and (c.2943A > C; p.Lys981Asn); one was an intronic missense variant (c.1402–2A > T) leading to an exonic deletion, and one was a deletion of 42 amino acids (c.1927-?_2052 + ?del.) All variants were novel and homozygous. The pathogenicity of these variants was determined according to the American College of Medical Genetics (ACMG) variant classification and in silico analysis. Another novel homozygous variant (c.1384C > G; p.Leu462Val) was detected, which was classified as likely benign.The novel variants identified in the GLDC in these patients underlie the pathogenesis of NKH, specifically for the Middle Eastern population. This expands the mutation spectrum of NKH to include a distinct ethnic population that has not been studied before.

Can Cinnamon Spice Down Autoimmune Diseases?

Autoimmune diseases are one of the dreadful group of human diseases that have always been of keen interest to researchers. Due to complex and broad-spectrum nature, scientists are not yet able to pinpoint the pathogenesis of and delineate effective therapy against this group of diseases. However, it is becoming clear that a decrease in number and function of T regulatory cells (Treg), an increase in autoreactive Th1/Th17 cells and associated immunomodulation and inflammation participate in the pathogenesis of many autoimmune diseases. Cinnamon (Cinnamonum verum or Cinnamonum cassia) is a widely used natural spice and flavoring ingredient and its metabolite sodium benzoate (NaB) is a food-additive and FDA-approved drug against nonketotic hyperglycinemia (NKH) and urea cycle disorders (UCD). Recent studies indicate that cinnamon either in powder or extract form and NaB are capable of modulating different autoimmune pathways as well as protecting animals from different autoimmune disorders. Here, we have made an honest attempt to delineate such pieces of evidence with available anti-autoimmune mechanisms and analyze whether cinnamon supplements could be used to control the fury of autoimmune disorders.

Nonketotic Hyperglycinemia in Tunisia. Report upon a Series of 69 Patients

Aim The aim of the study is to report on epidemiological, clinical, and biochemical characteristics of nonketotic hyperglycinemia (NKH) in Tunisia. Methods Patients diagnosed with NKH in Laboratory of Biochemistry at Rabta hospital (Tunis, Tunisia) between 1999 and 2018 were included. Plasma and cerebrospinal fluid (CSF) free amino acids were assessed by ion exchange chromatography. Diagnosis was based on family history, patient's clinical presentation and course, and increased CSF to plasma glycine ratio. Results During 20 years, 69 patients were diagnosed with NKH, with 25 patients originating from Kairouan region. Estimated incidences were 1:55,641 in Tunisia and 1:9,684 in Kairouan. Consanguinity was found for 73.9% of the patients and 42% of the families have history of infantile death due to a disease of similar clinical course than the propositus. Clinical symptoms initiated within the first week of life in 75% of the patients and within the first 3 months in 95.7% ones. The phenotype was severe in 76.8% of the patients. Main symptoms were hypotonia, feeding difficulties, coma, apnea, and seizures. Most patients died within few days to months following diagnosis. CSF to plasma glycine ratio was increased in all patients. CSF and plasma glycine levels were negatively correlated with age of disease onset and severity. Conclusion NKH is quite frequent in Tunisia. Kairouan region has the highest NKH incidence rate, worldwide. However, due to lack of confirmatory enzymatic and genetic tests, NKH diagnosis was based on first-line biochemical tests. Characterization of causal mutations is needed for accurate diagnosis and prenatal diagnosis of this devastating life-threatening disease.