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.

Nonketotic Hyperglycinemia of Infants in Taiwan.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a rare, inherited disease, with very poor outcome. It is difficult to confirm the diagnosis due to nonspecific presentations and rapid progression. The incidence was reported in a few countries. We report the clinical and genetic features of typical neonatal NKH with novel splicing mutation, c.1058+3A>C, in the intron 7 of the glycine decarboxylase (GLDC) gene. Furthermore, this study aimed to delineate the estimated incidence and clinical characteristics of NKH in the Taiwanese population. METHODS: Reports of Health Promotion Administration, Ministry of Health and Welfare of Taiwan, during the period from 2000 to 2013; the Human Gene Mutation Database; and literature regarding NKH in Taiwan were reviewed. Demographic information, age of onset, clinical characteristics, genetic analysis, electroencephalography examinations, and outcome of the patients were analyzed. RESULTS: The estimated incidence of NKH in the Taiwanese population was 7.2 cases per 1,000,000 live births. Among the 12 cases reported in Taiwan, more than 90% were of neonatal type. Fifty-five percent of affected patients died within 5 years, and all survivors had severe neurologic outcomes. Only three infants underwent genetic analysis during the study period. Two neonatal NKH infants had mutation in the GLDC gene, and the other one, who had late-onset NKH, had mutation in the glutaredoxin 5 gene. CONCLUSION: Compared with other countries, the estimated incidence of NKH was relatively rare in the Taiwanese population. It is important to characterize all index cases at the genetic level. With more awareness of NKH, increased knowledge of gene mutation, and improvement of diagnostic tools, NKH can be diagnosed more accurately.

Intracerebral blood and MRS in neonatal nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is an inborn error of glycine metabolism leading to the accumulation of glycine in the brain. The neonatal form presents in the first days after birth with encephalopathy, seizures. and characteristic "hiccups." Rapid progression can lead to intractable seizures, coma, and respiratory failure. The outcome is invariably poor, and many die before age 1 year. The diagnosis of nonketotic hyperglycinemia is traditionally based on the finding of a raised cerebrospinal fluid-to-plasma-glycine ratio. An elevated glycine peak, using long echo time proton magnetic resonance spectroscopy, is also specific to nonketotic hyperglycinemia. The presence of blood in a cerebrospinal fluid sample is known to render the glycine level uninterpretable. However, there have been no reports of intracerebral blood confounding the cerebral glycine detected on long echo time proton magnetic resonance spectroscopy. We report on an infant who presented with neonatal encephalopathy and imaging findings consistent with hypoxic-ischemic encephalopathy, as well as intracerebral hemorrhage and an abnormal glycine peak on spectroscopy. The source of the abnormal glycine on long echo time proton magnetic resonance spectroscopy was intracerebral blood, highlighting an important confounder in the interpretation of long echo time proton magnetic resonance spectroscopy in suspected nonketotic hyperglycinemia.

Late-onset nonketotic hyperglycinemia with leukodystrophy and an unusual clinical course.

Late-onset nonketotic hyperglycinemia is very rare, presents with varied clinical features, and may be underdiagnosed. A 2-year-old girl with normal development had acute gait disturbance progressing to severe spastic diplegia. Plasma glycine levels were elevated, with a normal cerebrospinal fluid:plasma glycine ratio. Cranial magnetic resonance imaging revealed leukodystrophy. Nonketotic hyperglycinemia was confirmed enzymatically. At age 7 years, she cannot walk, but has borderline normal intelligence. Leukodystrophy and a normal cerebrospinal fluid:plasma glycine ratio were not previously reported in late-onset nonketotic hyperglycinemia.

Natural history of nonketotic hyperglycinemia in 65 patients.

BACKGROUND: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an autosomal recessive disorder caused by a defect in the glycine cleavage system. NKH is classically associated with neonatal apnea, lethargy, hypotonia, and seizures, followed by severe psychomotor retardation in those who survive. METHODS: To determine the natural history of NKH, the authors mailed a 44-question survey to 170 households in the International NKH Family Network. RESULTS: Data for 65 patients (36 boys, 29 girls) were collected from 58 families. One-third of the subjects died; 8 girls died during the neonatal period, and 14 patients died thereafter (2 girls, 12 boys). Median age of death for boys was 2.6 years vs <1 month for girls (p = 0.02). Mean birth weight and length, occipitofrontal circumference, and gestation duration were normal. Two-thirds of infants were ventilated during the neonatal period; of these, 40% died. Ninety percent had confirmed seizures, 75% during the first month of life. Interestingly, three NKH patients never developed seizures. An abnormal corpus callosum and/or hydrocephalus were associated with especially poor gross motor and speech development. Of 25 patients living > or =3 years, 10 were able to walk and say/sign words; all were boys. In six families with more than one affected child, disease course and mortality were similar within each family. CONCLUSIONS: This study reveals a striking and unexpected gender difference in mortality and developmental progress. Of the two-thirds of nonketotic hyperglycinemia patients surviving the newborn period, up to 20% (mostly boys) may learn to walk and communicate by saying or signing words.