Nicotine and Cytisine Embryotoxicity in the Experimental Zebrafish Model.

Tobacco smoking is one of the most serious health problems. Potentially lethal effects of nicotine for adults can occur with as little as 30 to 60 mg, although severe symptoms can arise with lower doses. Furthermore, the route of administration also influences the toxicity. Cytisine is one of the most popular medications in nicotinism treatment. Like nicotine, cytisine is a plant alkaloid, signaling through nicotinic acetylcholine receptors. Our study evaluated the effects of cytisine in nicotine-induced embryotoxic effects using zebrafish larvae. We examined the teratogenicity of nicotine and cytisine alone or in combination. Nicotine increased mortality and delayed hatching of zebrafish larvae in a dose-dependent manner. Cytisine did not affect mortality in a wide range of concentrations, and hatching delay was observed only at the highest concentrations, above 2 mM. Administering compounds together partially reduced the adverse teratogenic effect induced by nicotine alone. The protective effect of cytisine against the nicotine effect, observed in zebrafish, will contribute to future studies or treatments related to nicotine addiction or prenatal nicotine exposure in humans.

Mucopolysaccharidosis-Plus Syndrome: Report on a Polish Patient with a Novel VPS33A Variant with Comparison with Other Described Patients.

Eleven patients from Yakutia with a new lysosomal disease assumed then as mucopolysaccharidosis-plus syndrome (MPS-PS) were reported by Gurinova et al. in 2014. Up to now, a total number of 39 patients have been reported; in all of them, the c.1492C>T (p.Arg498Trp) variant of the VPS33A gene was detected. Here, we describe the first Polish MPS-PS patient with a novel homozygous c.599G>C (p.Arg200Pro) VPS33A variant presenting over 12 years of follow-up with some novel clinical features, including fetal ascites (resolved spontaneously), recurrent joint effusion and peripheral edemas, normal growth, and visceral obesity. Functional analyses revealed a slight presence of chondroitin sulphate (only) in urine glycosaminoglycan electrophoresis, presence of sialooligosaccharides in urine by thin-layer chromatography, and normal results of lysosomal enzymes activity and lysosphingolipids concentration in dried blood spot. The comparison with other MPS-PS described cases was also provided. The presented description of the natural history of MPS-PS in our patient may broaden the spectrum of phenotypes in this disease.

Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice.

Metastasis is the leading cause of death in cancer patients, and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate-limiting step of this process. We used tail-vein injection of B16-F10 melanoma cells into mice to mimic the presence of CTCs and to allow for the assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (encoded by Cyba, Cybb, Ncf1, Ncf2, and Ncf4), all showed decreased pulmonary metastatic colonisation. To understand the role of NOX2 in controlling tumour cell survival in the pulmonary microenvironment, we focused on Cyba-deficient (Cybatm1a ) mice, which showed the most significant decrease in metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cybatm1a mice, owing to the presence of large granulomas composed of galectin-3 (Mac-2)-positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in Cybatm1a mice that were not injected with melanoma cells, and these contributed to their decreased survival. The decreased pulmonary metastatic colonisation of Cybatm1a mice was not due to any overt defects in vascular permeability, and bone marrow chimaeras confirmed a role for the haematological system in the reduced metastatic colonisation phenotype. Examination of the lymphocyte populations, which are known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and natural killer cells in the lungs of Cybatm1a mice, relative to controls. The reduced metastatic colonisation, presence of granulomas and altered immune cell populations observed in Cybatm1a lungs were mirrored in Ncf2-deficient (Ncf2tm1a ) mice. Thus, we show that NOX2 deficiency results in both granulomas and the accumulation of antitumoural immune cells in the lungs that probably mediate the decreased pulmonary metastatic colonisation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mild phenotype of glutaric aciduria type 1 in polish patients - novel data from a group of 13 cases.

Glutaric aciduria type 1 is a neurometabolic disorder, caused by riboflavin-dependent glutaryl-CoA dehydrogenase deficiency. As its consequence, accumulation of the putatively neurotoxic metabolites (glutaric and 3-hydroxyglutaric acids) in body tissues, but especially within the brain, is observed. Estimated incidence of the disease is 1 in 110,000 newborns, The prevalence however may be higher, depending on a specific ethnic group, and result in phenotypic variation as well. In this paper we present clinical data of 13 patients of Polish nationality. They all present a mild phenotype and clinical course of glutaric aciduria type 1. Based on their clinical data, presented herein, we like to pay attention to the phenotypic and neuroimaging features important for the diagnosis of mild form of this disease. Moreover, we present novel molecular data, which may correlate with such a manifestation.

Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA).

BACKGROUND: Resistance to thyroid hormone is characterised by a lack of response of peripheral tissues to the active form of thyroid hormone (triiodothyronine, T3). In about 85% of cases, a mutation in THRB, the gene coding for thyroid receptor ß (TRß), is the cause of this disorder. Recently, individual reports described the first patients with thyroid hormone receptor α gene (THRA) defects. METHODS: We used longitudinal clinical assessments over a period of 18 years at one hospital setting combined with biochemical and molecular studies to characterise a novel thyroid hormone resistance syndrome in a cohort of six patients from five families. FINDINGS: Using whole exome sequencing and subsequent Sanger sequencing, we identified truncating and missense mutations in the THRA gene in five of six individuals and describe a distinct and consistent phenotype of mild hypothyroidism (growth retardation, relatively high birth length and weight, mild-to-moderate mental retardation, mild skeletal dysplasia and constipation), specific facial features (round, somewhat coarse and flat face) and macrocephaly. Laboratory investigations revealed anaemia and slightly elevated cholesterol, while the thyroid profile showed low free thyroxine (fT4) levels coupled with high free T3 (fT3), leading to an altered T4 : T3 ratio, along with normal thyroid-stimulating hormone levels. We observed a genotype-phenotype correlation, with milder outcomes for missense mutations and more severe phenotypical effects for truncating mutations. INTERPRETATION: THRA mutations may be more common than expected. In patients with clinical symptoms of mild hypothyreosis without confirmation in endocrine studies, a molecular study of THRA defects is strongly recommended.

Mucopolysaccharidosis type VI in Russia, Kazakhstan, and Central and Eastern Europe.

BACKGROUND: The aim of this study was to describe the natural clinical course, incidence and prevalence of mucopolysaccharidosis type VI (MPS VI) in Russia, Kazakhstan, and Central and Eastern Europe. METHODS: Patients (n = 49) were identified by retrieving the data from eight international centers for MPS VI. RESULTS: A large number of patients presented with an attenuated phenotype (33%). Height and genotype were related to the severity of the disease, while no clear trend was observed between height and urinary glycosaminoglycan level. A high prevalence of the p.R152W mutation was observed both in the whole series (42%) as well as in Russian patients (43%). The incidence rate ranged from 0.0363 to 0.64 per 100,000 live births in Poland and Lithuania, respectively. CONCLUSIONS: The observed high p.R152W carrier frequency in the Lithuanian population may indicate a possible founder effect in this region. The high prevalence of this mutation observed in the whole series, as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin. Resettlement of the Polish population after World War II resulted in dilution of the prevalence of carriers in Poland and a very low MPS VI incidence.

Polish 2012 growth references for preschool children.

UNLABELLED: Growth references are useful in monitoring a child's growth, which is an essential part of child care. The aim of this paper is to provide updated growth references for Polish preschool children and to assess how well children in Poland match or diverge from the World Health Organization (WHO) growth standards/references and recent German height-for-age references. The height-, weight-, body mass index-for-age, and weight-for-height references were constructed with the LMS method using data from a recent, large, population-representative sample of 4,941 preschool children aged 3 to 6 years (the OLA study). In the case of boys, the third, 50th, and 97th height percentiles of new Polish and German references overlap almost completely, whereas the WHO growth standards/references percentiles are systematically lower. In the case of girls, comparison between the new Polish and German height references showed conformity on the third and 50th percentile, whereas body height values of the WHO standards/references are shorter. Polish children aged 3 to 6 years from for the nation representative sample, had significantly greater than zero mean z scores of height-, weight-, and BMI-for-age and weight-for-height, relative to the WHO growth standards/references. The number of children in the sample with height-for-age below -2 SD was significantly lower than expected and number of children with height-for-age above +2 SD was significantly higher than expected. CONCLUSION: The OLA study growth references can be recommended as national references for preschool children in Poland.

Relationship between Selected Cephalometric Parameters, Nasolabial Angle and Its Components in Adolescent Females.

Nasolabial angle is commonly used to assess the soft tissue profile of the subnasal region. The aim of this retrospective study was to evaluate the relationship between the nasolabial angle, the inclination of the lower border of the nose and upper lip, upper incisor inclination and upper lip thickness. A sample of 142 female adolescents aged 13-18 years was chosen. A modified cephalometric analysis was performed with the nasolabial angle, and its components were traced according to Fitzgerald's method. All analysed parameters showed a statistically significant correlation with the nasolabial angle (NLA). The highest correlation was found for the labial (L/FH) and nasal (N/FH) components of the nasolabial angle, respectively. Upper incisor inclinations (1+:SN, U1FA) and upper lip thickness (ULT) had a stronger correlation with L/FH than NLA, but no correlation was found between these parameters and N/FH. Upper lip thickness did not influence the relationship between incisor inclination and NLA or L/FH. The position of the upper incisors and upper lip thickness influence the nasolabial angle indirectly through its labial component (L/FH). Therefore, it seems purposeful to assess the nasolabial angle as a sum of two independent angles, of which only one (L/FH) can be influenced by orthodontic treatment.

Growth patterns in patients with mucopolysaccharidosis VII.

Objective: This study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy. Methods: Height, weight, and body mass index (BMI) measurements and Z-scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively. Results: Among 20 enrolled patients with MPS VII, height Z-scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z-score. BMI Z-scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z-scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z-scores in female patients. Conclusions: In patients with MPS VII, declines in height Z-score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z-score with age than did patients without a history of NIHF.Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.

Mucopolysaccharidosis type II in females and response to enzyme replacement therapy.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disease caused by a deficiency of iduronate-2-sulfatase (IDS). Two affected girls with moderate and severe forms of MPS II with normal karyotypes and increased urinary dermatan sulphate and heparin sulphate excretion and marked deficiencies of IDS activity are reported. Molecular studies showed that case 1 has a heterozygous mutation c.1568A > G (p.Y523C) associated with almost totally skewed inactivation of the normal maternal X chromosome, and case 2 has a heterozygous deletion that includes exons 1-4 of IDS (minimal deletion range c.1-103_184del). The multi-exon deletion correlated with early onset of the disease and severe phenotype with intellectual disability, whereas the missense mutation was associated with moderate developmental delay. Although genotype-phenotype correlation in MPS II is difficult, gene deletions seem to correlate with more severe clinical manifestation of the disease. Enzyme replacement therapy (ERT) in these two females resulted in disease stabilization in both.

Restricted joint range of motion in patients with MPS II: correlation with height, age and functional status.

AIM: The aims of the study were to assess shoulder range of motion (ROM) in patients with mucopolysaccharidosis type II (MPS II) and to correlate joint mobility with patients' height, age and functional status. METHODS: Passive ROM and Z-score of height were followed in 29 patients with MPS II (mean age 11.5 years, range 2-29 years) between the years 2005 and 2010. Passive ROM was measured by a goniometer, and height, by a stadiometer. Functional status was assessed by an age-appropriate health assessment questionnaire (HAQ). RESULTS: (i) A strong correlation was observed between patients' age and Z-score of patients' height (R = 0.78, p < 0.001). (ii) A medium correlation was observed between Z-score of patients' height and passive shoulder flexion and abduction (R = 0.697, p < 0.001 and R = 0.63, p < 0.001, respectively). The progression of restriction was slower in attenuated patients. (iii) Restrictions in shoulder flexion and abduction were already observed before the second year of life. (iv) ROM limitations intensified and became more severe with age. (v) Activities of daily living depended on cognitive impairment of patients with MPS II. CONCLUSION: Range of motion limitations in patients with MPS II correlate with patients' height, increase with patients' age and are more pronounced in a severe form of MPS II.

Comparison of growth dynamics in different types of MPS: an attempt to explain the causes.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficient activity of enzymes responsible for the catabolism of glycosaminoglycans (GAGs), resulting in progressive damage to various tissues and organs. Affected individuals present with skeletal deformities, bone growth impairment, joint stiffness and frequently mental retardation. RESULTS: The objective of the study was to summarise over 30 years of observations of the growth dynamics in patients with different types of MPS, performed at the Children's Memorial Health Institute (CMHI, Warsaw, Poland). A retrospective analysis of anthropometric data collected from 1989 to 2020 was performed for 195 patients with MPS I, MPS II, MPS III, MPS IVA and MPS VI. Mean values for birth body length were statistically significantly greater than in the general population. The mean z-scores for other MPS groups showed that until the 24th month of life, the growth pattern for all patients was similar, and the average z-scores for body height were greater than in reference charts. Afterwards, growth patterns began to differentiate for MPS groups. CONCLUSIONS: The long-term follow up showed that the growth pattern in patients with all types of mucopolysaccharidoses significantly deviates from the general population. Patients with MPS IVA had the most severe growth impairments compared to other patients in the study group. Neuropathic MPS I and II demonstrated severe growth impairments compared to other patients in this study. Patients with MPS III showed the mildest growth impairments compared to other MPS patients and reached the 3rd percentile last.

Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG.

Congenital Disorders of Glycosylation (CDG) are multisystemic metabolic disorders showing highly heterogeneous clinical presentation, molecular etiology, and laboratory results. Here, we present different transferrin isoform patterns (obtained by isoelectric focusing) from three female patients harboring the ALG13 c.320A>G mutation. Contrary to other known variants of type I CDGs, where transferrin isoelectric focusing revealed notably increased asialo- and disialotransferrin fractions, a normal glycosylation pattern was observed in the probands. To verify this data and give novel insight into this variant, we modeled the human Alg13 protein and analyzed the dynamics of the apo structure and the complex with the UDP-GlcNAc substrate. We also modeled the Alg13-Alg14 heterodimer and ran multiple simulations of the complex in the presence of the substrate. Finally, we proposed a plausible complex formation mechanism.

Long-term outcome of patients with alpha-mannosidosis - A single center study.

INTRODUCTION: Alpha-mannosidosis (AM) is a rare autosomal recessive lysosomal storage disease which the natural history has not been exhaustively described yet. The aim of this study was to present the long-term follow-up of 12 Polish patients with AM, evaluate the clinical, biochemical, and molecular findings and progression of the disease. MATERIAL AND METHODS: The article presents a long-term (over 30 years) observational, retrospective, single-center study of patients with AM. RESULTS: The hearing loss, as one of the first symptoms, was detected in childhood (mean age of 2 years and 6 months) in 10 patients. The other symptoms include: recurrent infections (all patients), inguinal hernias (6 patients), craniosynostosis (1 patient). The mean age at AM diagnosis was 6 years while median was 4 years (age range: 1 year and 8 months - 12 years). The most commonly identified variant in the MAN2B1 gene was c.2245C > T, p.(Arg749Trp). The mean time of follow-up in our study was approximately 14 years (range: 1 year - 26 years). Following birth, children with AM grow slowly, finally reaching the 3rd percentile (or values below the 3rd percentile). Hearing loss was not progressive while a gradual exacerbation of intellectual disability with no developmental regression was observed in all patients. Ataxia was diagnosed in 6 patients in the second decade of life (age range 15-20 years). CONCLUSIONS: Our study revealed the sensorineural hearing loss as one of the first noted symptom in AM which was congenital and non-progressive during the natural course of disease. A detailed anthropometric phenotype of AM patients was provided with observation of the growth decline during the long-term follow-up. Our study confirmed the existence of two distinguished clinical phenotypes of AM (mild and moderate), and also the lack of clear genotype-phenotype correlation.

Anthropometric Phenotype of Patients with PMM2-CDG.

BACKGROUND: Growth failure is commonly reported in children with PMM2-CDG. The aim of the study was to delineate the longitudinal anthropometric phenotype of patients with PMM2-CDG and attempt to find some correlations between the genotype and anthropometric phenotype. MATERIALS AND METHODS: Retrospective chart review of PMM2-CDG patients' medical records was performed regarding the anthropometric measurements (head circumference, body length/height, body weight, body mass index) and PMM2 variants. RESULTS: A negative tendency of growth evolution was observed. Patients found to be heterozygous for R141H grew slower than other patients. Body weight was correlated with body height. A negative tendency of the growth rate of head circumference was observed. Patients found to be heterozygous for R141H experienced slower growth than other patients. CONCLUSIONS: Long-term observational studies are essential to characterize the anthropometric phenotype. The body growth failure, as well as head circumference growth failure, were more severe in patients found to be heterozygous for R141H.

Diverse clinical outcome of Hunter syndrome in patients with chromosomal aberration encompassing entire and partial IDS deletions: what is important for early diagnosis and counseling?

Our study aims to delineate the syndromology of Hunter syndrome (MPSII), by presenting three patients with different clinical courses, caused by different genetic mechanisms. Single-nucleotide variants (SNV) or small deletions encompassing the iduronate-2-sulfatase (IDS) gene are identified in the majority of affected individuals, while deletion of contiguous genes or whole IDS gene (described herein) has been reported rarely, mainly in patients with a severe Hunter syndrome presentation. There is; however, lack of reliable genotype-phenotype correlation, especially regarding anthropometric parameters, and thus our understanding of MPSII pathophysiology is not complete. On the basis of our observations, we would like to draw attention to the fact that neurological manifestations observed in patients with contiguous gene deletions, encompassing the IDS gene, may significantly differ from those observed in SNV. The phenotype is; however, difficult to predict and depends on the type (deletion/duplication), size (small/large) of aberration, and gene content. Moreover, it also has implications for genetic counseling, and recurrence risk in those families differs from the usual situation and must be clarified by parental chromosomal studies.

CRISPR activation screen in mice identifies novel membrane proteins enhancing pulmonary metastatic colonisation.

Melanoma represents ~5% of all cutaneous malignancies, yet accounts for the majority of skin cancer deaths due to its propensity to metastasise. To develop new therapies, novel target molecules must to be identified and the accessibility of cell surface proteins makes them attractive targets. Using CRISPR activation technology, we screened a library of guide RNAs targeting membrane protein-encoding genes to identify cell surface molecules whose upregulation enhances the metastatic pulmonary colonisation capabilities of tumour cells in vivo. We show that upregulated expression of the cell surface protein LRRN4CL led to increased pulmonary metastases in mice. Critically, LRRN4CL expression was elevated in melanoma patient samples, with high expression levels correlating with decreased survival. Collectively, our findings uncover an unappreciated role for LRRN4CL in the outcome of melanoma patients and identifies a potential therapeutic target and biomarker.

A Genome-Wide Screen in Mice To Identify Cell-Extrinsic Regulators of Pulmonary Metastatic Colonisation.

Metastatic colonization, whereby a disseminated tumor cell is able to survive and proliferate at a secondary site, involves both tumor cell-intrinsic and -extrinsic factors. To identify tumor cell-extrinsic (microenvironmental) factors that regulate the ability of metastatic tumor cells to effectively colonize a tissue, we performed a genome-wide screen utilizing the experimental metastasis assay on mutant mice. Mutant and wildtype (control) mice were tail vein-dosed with murine metastatic melanoma B16-F10 cells and 10 days later the number of pulmonary metastatic colonies were counted. Of the 1,300 genes/genetic locations (1,344 alleles) assessed in the screen 34 genes were determined to significantly regulate pulmonary metastatic colonization (15 increased and 19 decreased; P < 0.005 and genotype effect <-55 or >+55). While several of these genes have known roles in immune system regulation (Bach2, Cyba, Cybb, Cybc1, Id2, Igh-6, Irf1, Irf7, Ncf1, Ncf2, Ncf4 and Pik3cg) most are involved in a disparate range of biological processes, ranging from ubiquitination (Herc1) to diphthamide synthesis (Dph6) to Rho GTPase-activation (Arhgap30 and Fgd4), with no previous reports of a role in the regulation of metastasis. Thus, we have identified numerous novel regulators of pulmonary metastatic colonization, which may represent potential therapeutic targets.

Modeling Morquio A Syndrome: An Anthropometric Study of Body Characteristics and Stature.

BACKGROUND: Morquio A syndrome or mucopolysaccharidosis (MPS) IVA is an autosomal recessive, life-limiting lysosomal storage disease caused by deficient activity of the enzyme galactosamine-6-sulfatase. Common early symptoms such as abnormalities of body stature can facilitate timely diagnosis. This study aimed to create a pattern of face and body stature based on anthropometric measurements taken from a cohort of Polish patients with MPS IVA. METHODS: Analysis of 11 somatometric and 14 craniofacial features was performed on 20 patients with MPS IVA, aged from 3 months to 26 years. The diagnosis of MPS IVA was confirmed by enzymatic and molecular analysis. Two-tailed t-tests were used to compare mean values for body length and weight at birth between the MPS IVA patients and the general population. To show the degree and direction of deviation z-scores were calculated and then used to construct a model of an average MPS IVA patient. RESULTS: Mean values for body height and weight at birth were greater for boys than for the general population. The observed pattern of head and body shape indicated that dwarfism occurred with age as a result of the relatively short trunk and lower limbs. Skeletal abnormalities included a bell-shaped chest with the ratio of chest depth to chest width being significantly above the norm. The head and neck were relatively elongated, in comparison to body height, and tucked between narrow shoulders. The head had dolichocephalic shape, while the nose was short with wide nostrils. CONCLUSIONS: Multiple anthropometric measurements, including age ranges, allowed for the creation of a model that showed the most characteristic features of the MPS IVA phenotype.

NGLY1 deficiency: Novel patient, review of the literature and diagnostic algorithm.

OBJECTIVES: Together with the lysosomal storage diseases, NGLY1 deficiency is a congenital disorder of deglycosylation (NGLY1-CDDG). Since the first report in 2012, 26 patients have been described. All but one were diagnosed by exome or genome sequencing; the remaining one was identified by finding an increased concentration of an urinary marker.The aim of this study was to describe the clinical, biochemical, and molecular features of the first Polish patient diagnosed with NGLY1-CDDG, to provide an overview of the literature and to propose a diagnostic algorithm. RESULTS: A Polish patient presented with global developmental delay, hyperkinetic movement disorder, stagnation of head growth, hypolacrimia, elevated serum transaminases, and hypolipidemia in infancy. Whole exome sequencing revealed two heterozygous nonsense variants in the NGLY1 gene (a novel and an unreported). Literature review revealed global developmental disability in all reported patients, and hyperkinetic movements as well as alacrima/hypolacrima in nearly all. CONCLUSIONS: NGLY1-CDDG should be considered in patients with developmental disability associated with a hyperkinetic movement disorder and alacrimia/hypolacrima. Absence of the latter two symptoms does not rule out this diagnosis.