Homozygosity for disease-causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is a relatively well-characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system-GLDC, AMT, and GCSH-are independently associated with NKH. We report on a patient with severe NKH in whom the homozygous pathogenic variant in AMT (NM_000481.3):c.602_603del (p.Lys201Thrfs*75) and the homozygous likely pathogenic variant in GLDC(NM_000170.2):c.2852C>A (p.Ser951Tyr) were both identified. Our patient demonstrates a novel combination of two homozygous disease-causing variants impacting the glycine cleavage pathway at two different components, and elicits management- and genetic counseling-related challenges for the family.

Metabolic disease in the Pacific: Lessons for indigenous populations.

Twenty-five percent of the New Zealand population is either Maori or Pacific and are thus indigenous to the region. The New Zealand National Metabolic Service has considerable experience in diagnosing and managing metabolic diseases in this population. The frequencies and phenotypes of inborn errors of metabolism in indigenous people differ from that in Western European populations. Metabolic services need to be aware of these local variations and adapt their screening and treatment protocols accordingly. Likewise, the services themselves need to adopt culturally appropriate practices. This includes an understanding of the language, ideally employment of indigenous people and targeting of the service to meet the needs of the people. Knowledge of the metabolic diseases common within particular ethnic groups is important for the rapid delivery of appropriate management. Newborn screening protocols need to reflect the local populations. With the advent of expanded newborn screening relatively benign forms of fatty acid oxidation disorders have been commonly encountered. This high prevalence may reflect a selective evolutionary advantage as similar conditions have been found in other ethnic groups with traditionally high fat and low carbohydrate diets. HLA haplotypes of indigenous populations are less represented in international stem cell transplant databanks thereby making the option of human stem cell transplant more challenging. The recent discovery that short-chain enoyl-CoA hydratase deficiency is particularly common in New Zealand with nearly a dozen cases identified this year suggests there is still a lot to learn regarding Maori and Pacific and indeed an indigenous metabolic disease.

Biallelic start loss variant, c.1A > G in GCSH is associated with variant nonketotic hyperglycinemia.

The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh-like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A > G in GCSH.

Case report: Unveiling genetic and phenotypic variability in Nonketotic hyperglycinemia: an atypical early onset case associated with a novel GLRX5 variant.

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT, GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3. We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM_016417.3:c.367G>C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH's genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH.

gldc Is Essential for Renal Progenitor Patterning during Kidney Development.

The glycine cleavage system (GCS) is a complex located on the mitochondrial membrane that is responsible for regulating glycine levels and contributing one-carbon units to folate metabolism. Congenital mutations in GCS components, such as glycine decarboxylase (gldc), cause an elevation in glycine levels and the rare disease, nonketotic hyperglycinemia (NKH). NKH patients suffer from pleiotropic symptoms including seizures, lethargy, mental retardation, and early death. Therefore, it is imperative to fully elucidate the pathological effects of gldc dysfunction and glycine accumulation during development. Here, we describe a zebrafish model of gldc deficiency that recapitulates phenotypes seen in humans and mice. gldc deficient embryos displayed impaired fluid homeostasis suggesting renal abnormalities, as well as aberrant craniofacial morphology and neural development defects. Whole mount in situ hybridization (WISH) revealed that gldc transcripts were highly expressed in the embryonic kidney, as seen in mouse and human repository data, and that formation of several nephron segments was disrupted in gldc deficient embryos, including proximal and distal tubule populations. These kidney defects were caused by alterations in renal progenitor populations, revealing that the proper function of Gldc is essential for the patterning of this organ. Additionally, further analysis of the urogenital tract revealed altered collecting duct and cloaca morphology in gldc deficient embryos. Finally, to gain insight into the molecular mechanisms underlying these disruptions, we examined the effects of exogenous glycine treatment and observed analogous renal and cloacal defects. Taken together, these studies indicate for the first time that gldc function serves an essential role in regulating renal progenitor development by modulating glycine levels.

Location-atypical lesions in non-ketotic hyperglycemic epilepsy: expanding the clinico-radiographic phenotype

Non-ketotic hyperglycemia (NKH) is associated with a spectrum of symptoms and radiographic findings due to poorly-controlled diabetes mellitus. These lesions, which predominantly affect the parieto-occipital cortex, are commonly missed by neurologists and neuroradiologists due to their subtle hypointense appearance on T2-based imaging. We report four atypical cases of this syndrome to highlight its subtle, protean presentation in order to aid timely diagnosis. Based on our institutional case series, we describe four cases of NKH with atypical presentation and lesion burden affecting the anterior cortex. We review the clinical presentations, laboratory abnormalities, neuroimaging, and corresponding electroencephalography. Four patients with atypical NKH were characterized in our series. Presenting symptoms ranged from rhythmic hand-tapping to generalized tonic-clonic status epilepticus. Laboratory values were notable for marked hyperglycemia (range: 447 - 627 mg/dL), mild pseudo-hyponatremia (range: 127 - 136 mmol/L), and elevated hemoglobin A1C levels (range: 10.9 - 16.1%). All patients were found to have the classically described pattern of T2-based hypointensity; three with atypical distributions involving the "anterior" cortex. These lesions corresponded to the electrographic nidus of seizure burden. During follow-up, both seizures and T2-based hypointensity resolved within weeks of serum glucose normalization. Our series of four NKH patients with atypical findings of T2-based signal abnormalities expands the clinico-radiographic phenotype revealing a more protean distribution than previously described. Knowledge of these atypical imaging features will aid both the neurologist and radiologist in timely diagnosis and care of these patients.

Consideration of a metabolic disorder in the differential of mild developmental delay: A case of nonketotic hyperglycinemia revisited 36 years later.

We present a 53-year-old male with nonketotic hyperglycinemia (NKH) who presented in decompensated state to our university hospital several months prior to a primary diagnosis of multifocal pneumonia accompanied by reports of seizure-like activity, altered mental status, tremors, and fever. He was initially diagnosed with NKH in his preschool years, over 40 years previously, along with his younger sister. At that time, he had developmental and physical delays (which his sister also experienced). His health course has been relatively uneventful otherwise, as regards decompensation of his disease, and he has not been on the standard regimens of reduced dietary glycine intake along with dextromethorphan and sodium benzoate. Recent molecular confirmation of NKH was completed and both he and his sibling likely have an attenuated form of NKH mediated by the combined effects of their variants. This paper presents what we believe to be report of the oldest surviving individuals with attenuated NKH.

A Case Report of Nonketotic Hyperglycemic Seizures: A Diagnostic Dilemma.

Nonketotic hyperglycemia (NKH) is a rare but serious complication of uncontrolled diabetes mellitus that occurs acutely with a mortality rate of more than 50%. This condition presents with a clinical syndrome consisting of profound hyperglycemia, hyperosmolality, and dehydration. Infrequently, the patients also present with seizure activity. The most common types of seizures observed in this condition are focal seizures, as opposed to the generalized seizures observed in hypoglycemia-induced seizures. Though various hypotheses tried to explain NKH-induced seizure activity, the actual mechanism remains unknown. The treatment modalities include the management of hyperglycemia and circulatory collapse. However, the role of anti-epileptics is controversial. We herein illustrate an atypical case of focal faciobrachial seizures in a young female patient, which occurred as a rare complication of NKH. A 21-year-old female was admitted with multiple jerking and spasmodic movements of the right upper limb and face, with no significant neurological findings. Past medical history was significant for uncontrolled type 2 diabetes mellitus and multiple episodes of focal seizures. On laboratory examination, serum osmolarity was 309 mOsm/L, blood glucose was 364 mg/dL, HbA1c was 12.1%, and ketone bodies were absent. MRI brain showed large subtle T2 FLAIR (T2-weighted fluid-attenuated inversion recovery) cortical hyperintensities in the left frontal, temporal, parietal, and occipital regions with subcortical hypointense areas. The EEG illustrated a background slowing and generalized spikes, polyspikes, and sharp-wave discharges with post-ictal slowing. The patient's seizures were initially refractory to insulin therapy and resolved with the use of dual anti-epileptics. Thus, to conclude, our case represents a diagnostic dilemma with MRI findings pointing towards NKH as the underlying etiology of focal seizures, with the resolution of seizures only occurring with the addition of anti-epileptics to insulin therapy.

Nonketotic Hyperglycinemia: Two Case Reports and Review.

Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder of glycine metabolism resulting in an excessive accumulation of glycine in all body tissues, including the central nervous system. It is caused by a biochemical defect in the glycine cleavage system and considered as a rare disorder with an estimated prevalence of 1:60,000. The neonatal form presents in the first few days of life with progressive encephalopathy, hypotonia, myoclonic jerks, hiccups, seizures, rapid progression to coma and often death due to central apnea. Surviving infants often have severe developmental delay and refractory seizures. Atypical forms of NKH present with heterogeneous and nonspecific disease course. Classical glycine encephalopathy usually carries a very poor prognosis. We describe two neonates who presented with neonatal encephalopathy, apnea, and progressive lethargy. Increased CSF glycine level along with an elevated CSF to plasma glycine ratio was suggestive of classic NKH. Burst suppression EEG and agenesis of the corpus callosum were supportive findings. Evolution of the EEG patterns and course of the disease are discussed in detail. Transient phases of clinical stabilization and normalized plasma biochemical results may not necessarily reflect the actual encephalopathic process. Serial EEGs are helpful to assess the efficacy of treatment and to modify the therapeutic approach.

Occipital lobe seizures and subcortical T2 and T2* hypointensity associated with nonketotic hyperglycemia: a case report.

BACKGROUND: Nonketotic hyperglycemia often causes seizures. Recently, seizures associated with nonketotic hyperglycemia have been found to be associated with subcortical T2 hypointensity on magnetic resonance imaging, especially in the occipital lobes. However, the mechanism remains unclear, although iron accumulation is suggested. We present a case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the hypothesis that the mechanism of subcortical T2 hypointensity is iron accumulation using gradient-echo T2*-weighted magnetic resonance imaging. CASE PRESENTATION: A 65-year-old Japanese man complained of intermittent pastel-colored flashing lights. On neurological examination, he also had lower right-side quadrant hemianopia. No other abnormal neurological findings were found. On laboratory analysis, his blood glucose level was 370 mg/dL, HbA1c was 11.4 %, and serum osmolarity was 326 mOsm/L. No ketones were detected in urine. A magnetic resonance imaging scan of his head showed subcortical T2 and T2* hypointensity in his left occipital lobe. Single-photon emission computed tomography with I123-N-isopropyl-iodoamphetamine revealed hyperperfusion in the left dominant occipital lobe. These magnetic resonance imaging abnormalities resolved during clinical recovery and treatment to control his blood sugar level. Therefore, a diagnosis of occipital lobe seizures associated with nonketotic hyperglycemia was made. CONCLUSIONS: To the best of our knowledge, this is the first case of occipital lobe seizures associated with nonketotic hyperglycemia supporting the role of iron accumulation as a mechanism for subcortical T2 hypointensity using T2*-magnetic resonance imaging.

The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders.

INTRODUCTION: Neurotransmitters are chemical messengers that enable communication between the neurons in the synaptic cleft. Inborn errors of neurotransmitter biosynthesis, breakdown and transport are a group of very rare neurometabolic diseases resulting in neurological impairment at any age from newborn to adulthood. METHODS AND RESULTS: The International Working Group on Neurotransmitter related Disorders (iNTD) is the first international network focusing on the study of primary and secondary neurotransmitter disorders. It was founded with the aim to foster exchange and improve knowledge in the field of these rare diseases. The newly established iNTD patient registry for neurotransmitter related diseases collects longitudinal data on the natural disease course, approach to diagnosis, therapeutic strategies, and quality of life of affected patients. The registry forms the evidence base for the development of consensus guidelines for patients with neurotransmitter related disorders. CONCLUSION: The iNTD network and registry will improve knowledge and strengthen research capacities in the field of inborn neurotransmitter disorders. The evidence-based guidelines will facilitate standardized diagnostic procedures and treatment approaches.