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RM; Trastornos hereditarios de neurotransmisores; Monoaminas; Deficiencia de tetrahidrobiopterina RM; Trastorns dels neurotransmissors heretats; Monoamines; Deficiència de tetrahidrobiopterina MRI; Inherited neurotransmitter disorders; Monoamines; Tetrahydrobiopterin deficiency; Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction. © 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders. © 2021, The Author(s).

Following the original article's publication [1] the authors asked for the correction of Fig. 2, since the names of the disease genes [GCH1 and PCBD1] in the figure published did not match the listed diseases [AR-GTPCHD and PCDD]. The correct Fig. 2 isshown below: In the context of the manuscript correction and inorder to match he text content, the words "apart from DHPRD" should be removed from the second row and second column of Table 4, as shown below: (Table Presented). © 2020 The Author(s). Reference.

Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a severe metabolic disease manifesting as muscle hypotonia, developmental delay, cerebellar ataxia and ocular symptoms; typically, nystagmus and optic disc pallor. Recently, early onset retinal dystrophy has been reported as an additional feature. In this study, we summarize ocular phenotypes and SRD5A3 variants reported to be associated with SRD5A3-CDG. We also describe in detail the ophthalmic findings in a 12-year-old Czech child harbouring a novel homozygous variant, c.436GA, p.(Glu146Lys) in SRD5A3. The patient was reviewed for congenital nystagmus and bilateral optic neuropathy diagnosed at 13 months of age. Examination by spectral domain optical coherence tomography and fundus autofluorescence imaging showed clear signs of retinal dystrophy not recognized until our investigation. Best corrected visual acuity was decreased to 0.15 and 0.16 in the right and left eye, respectively, with a myopic refractive error of -3.0 dioptre sphere (DS) / -2.5 dioptre cylinder (DC) in the right and -3.0 DS / -3.0 DC in the left eye. The proband also had optic head nerve drusen, which have not been previously observed in this syndrome.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a disorder with autosomal recessive inheritance caused by mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency results in imbalance of mitochondrial pool of nucleotides leading secondary to multiple deletions and depletion of mitochondrial DNA (mtDNA) and impairment of oxidative phosphorylation system. The disease is clinically characterized by gastrointestinal dysmotility with symptoms of pseudo-obstruction, severe failure to thrive, ptosis, leukoencephalopathy, peripheral neuropathy and myopathy. We present results of the clinical, histochemical, biochemical and molecular analyses of the first Czech patient with MNGIE syndrome.Man, 33-years old with twenty-year history of failure to thrive (height 168 cm, weight 34 kg) and progressive gastrointestinal dysmotility, external ophthalmoplegia, leucoencephalopathy and peripheral neuropathy was recommended to metabolic center. Histochemical analyses in muscle biopsy showed the presence of "ragged red fibers" with focal decrease of cytochrome c oxidase activity, but spectrophotometric analyses in isolated muscle mitochondria revealed normal activities of all respiratory chain complexes. Metabolic investigation revealed markedly increased plasma level of thymidine (6.6 micromol/l, controls0.05 micromol/l) and deoxyuridine (15 micromol/l, controls0.05 micromol/l). The activity of TP in isolated lymphocytes was low (0.02 micromol/hour/mg protein, reference range 0.78 +/- 0.18). Molecular analyses in muscle biopsy revealed multiple mtDNA deletions and homozygous mutation 1419GA (Gly145Arg) was found in gene for TP. Both parents are heterozygotes.MNGIE has to be considered in patients presenting with a combination of gastrointestinal and neurological symptoms. Plasma level of thymidine may serve as the best method for laboratory screening of MNGIE, but molecular analyses are necessary for genetic counselling and prenatal diagnosis in affected families.

Carnitine plays an important role in energetic metabolism. The aim of the study was to characterize the carnitine status in term and preterm newborns with respect to gestational age, birth weight, haematocrit and red blood cell count (RBC). The effect of nutrition on carnitine levels in the first week of life was also studied. Total blood pool of free carnitine (FC), acylcarnitines (AC) and total carnitine (TC) were analysed in whole cord blood and postnatally in capillary blood obtained at the day 4-6 in 33 term newborns and at the day 7-10 in 27 preterm newborns using tandem mass spectrometry. Plasma level of carnitine in the cord blood was measured using radioenzymatic method. Cord plasma levels of FC, AC and TC were higher in preterm newborns in comparison with term newborns (p0.01), but the total blood pool of FC and TC in whole cord blood was lower in preterm newborns than in term newborns (p0.01) and positive correlation was found between FC and gestational age or birth weight (p0.05). In addition, positive correlation was found between AC and red blood cell count or haematocrit (p0.05). During the first week of life, blood pool of FC and TC in term newborns and AC and TC in preterm newborns decreased regardless of the type of enteral or parenteral nutrition. Our results indicate that preterm newborns are born with limited carnitine store. Interpretation of carnitine analyses in whole blood relies in addition to gestational age and birth weight on the haematocrit, especially in newborns with anaemia or blood hyperviscosity.

Congenital disorders of glycosylation (CDG syndrome) represent a newly delineated group of inherited diseases of glycoprotein synthesis. We present results of biochemical and molecular analyses in two Czech patients with CDG Ia syndrome.Serum concentrations of the nonglycosylated and hypoglycosylated transferrin were measured using turbidimetric immunoassay. In positive patients, the isoelectric focusing of serum transferrin and molecular analyses of the gene for phosphomannomutase 2 were performed. The disease manifested in both children in infancy with failure to thrive, inverted nipples, strabismus, epilepsy, muscle hypotonia, microcephaly, psychomotor retardation and hypoplasia of the cerebellum. The biochemical investigation revealed elevated liver enzymes, low concentration of factor XI and protein S. In one child lower concentration of the antithrombin III and protein C were found. Activities of arylsulfatase A and beta-glucuronidase in serum were higher and activity of alpha-mannosidase in leucocytes was lower in comparison with controls. Molecular analyses revealed that both children are compound heterozygotes for the mutation 422GA and 357CA in gene for phosphomanomutase 2. Both siblings are also homozygotes for polymorfism IVS5 + 19 C--T and heterozygygotes for polymorfism IVS5 + 22 T--A.The prognosis of children with CDG Ia is unfavourable. Enzymatic and/or molecular studies are necessary for genetic counselling and the prenatal diagnosis.

Zinc is an essential trace element for the immune system. The zinc deficiency diminishes antibody- and cell-mediated responses in man. Lymphopenia and thymic atrophy are usually the early hallmarks of zinc deficiency. Surprisingly, only scarce data are available about polymorphonuclear cells (PMNs) functions in infants with zinc deficiency. We present the results of immunological analyses in one infant with transient zinc deficiency due to decreased zinc concentration in mother milk resulting in severe lactogenic acrodermatitis enteropathica.Nine repeated examination of oxidative burst of PMNs and immunoglobulin levels using nitroblue tetrazolium dye test, chemiluminescence, flow cytometry and nephelometry were performed in the infant with severe zinc deficiency during 28 months period.The unusual prolonged but transient impairment of PMNs respiratory burst accompanied with hypogammaglobulinaemia developed since the age of 2.5 months. Dramatic improvement of the skin was observed within days with total resolution of skin lesions on the 9th day of zinc therapy, but decreased PMNs respiratory burst persisted until the age of 23 months.We conclude that zinc deficiency may lead to prolonged impairment of polymorphonuclear cells functions and hypogammaglobulinaemia.

The most common cause of pyruvate dehydrogenase complex (PDHc) deficiency is the deficit of the E1α-subunit. The aim of this study was to describe distinct course of the disease in two boys with mutations in PDHA1 gene and illustrate the possible obstacles in measurement of PDHc activity. Clinical data and metabolic profiles were collected and evaluated. PDHc and E1α-subunit activities were measured using radiometric assay. Subunits of PDHc were detected by Western blot. PDHA1 gene was analysed by direct sequencing. In patient 1, the initial hypotonia with psychomotor retardation was observed since early infancy. The child gradually showed symptoms of spasticity and arrest of psychomotor development. In patient 2, the disease manifested by seizures and hyporeflexia in the toddler age. The diagnosis was confirmed at the age of seven years after attacks of dystonia and clinical manifestation of myopathy with normal mental development. Brain MRI of both patients revealed lesions typical of Leigh syndrome. Enzymatic analyses revealed PDHc deficiency in isolated lymphocytes in the first but not in the second patient. The direct measurement of PDH E1-subunit revealed deficiency in this individual. In patient 1, a novel hemizigous mutation c.857CT (Pro250Leu) was detected in the X-linked PDHA1 gene. Mutation c.367CT (Arg88Cys) was found in patient 2. We present first two patients with PDHc deficit due to mutations in PDHA1 gene in the Czech Republic. We document the broad variability of clinical symptoms of this disease. We proved that normal PDHc activity may not exclude the disease.

Lipoprotein lipase (LPL) deficiency, caused by mutations in the LPL gene, is a rare autosomal recessive disorder manifesting in early childhood with recurrent abdominal pain, hepatosplenomegaly, acute pancreatitis, lipaemia retinalis and eruptive xanthomas. Typical laboratory findings are lactescent serum, extreme hypertriglyceridaemia and hypercholesterolaemia. The diagnostics is based on postheparin serum LPL assay and DNA analyses of the LPL gene. We report clinical, biochemical and molecular data of three children with LPL deficiency. One child manifested since the first week of life with recurrent abdominal pain (Patient 1), the second with abdominal distension and hepatosplenomegaly since the second month of life (Patient 3) and patient 2, asymptomatic younger brother of patient 1, was diagnosed in the first week of life. Lipaemia retinalis and splenomegaly were present in two symptomatic children, hepatomegaly in patient 3 and acute pancreatitis in patient 1. All children had lactescent serum, profound hypertriglyceridaemia (124 ± 25 mmol/l; controls2.2), hypercholesterolaemia (22.8 ± 7.3 mmol/l, controls4.2) and their LPL immunoreactive mass in serum did not increase after heparin injection. Molecular analyses revealed that both siblings are homozygous for novel mutation c.476CG in the LPL gene changing the conserved amino acid of the catalytic centre. The third patient is a compound heterozygote for mutations c.604GA and c.698AG in the LPL gene, both affecting highly conserved amino acids. We conclude that LPL deficiency must be considered in neonates and young infants with abdominal pain and hypertriglyceridaemia because early treatment might prevent development of life-threatening acute pancreatitis.

BackgroundTetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4deficiencies.ConclusionAlthough the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4deficient patients.