Publications by authors named "Jan Kulhanek"

10 Publications

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Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines.

Nat Commun 2021 Sep 20;12(1):5529. Epub 2021 Sep 20.

University Children's Hospital Heidelberg, Dietmar-Hopp Metabolic Center, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1038/s41467-021-25515-5DOI Listing
September 2021

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

J Inherit Metab Dis 2021 Jul 9. Epub 2021 Jul 9.

University Children's Hospital, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.
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http://dx.doi.org/10.1002/jimd.12416DOI Listing
July 2021

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

J Inherit Metab Dis 2021 Jul 28;44(4):1070-1082. Epub 2021 Jan 28.

Inborn Errors of Metabolism Unit, Department of Neurology, Institut de Recerca Sant Joan de Déu and CIBERER-ISCIII, Barcelona, Spain.

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.
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http://dx.doi.org/10.1002/jimd.12360DOI Listing
July 2021

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH) deficiencies.

Orphanet J Rare Dis 2020 05 26;15(1):126. Epub 2020 May 26.

Division of Child Neurology and Metabolic Disorders, University Children's Hospital, Heidelberg, Germany.

Background: Tetrahydrobiopterin (BH) 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 BH biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH deficiencies, 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 BH deficiencies.

Conclusion: Although 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 BH deficient patients.
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http://dx.doi.org/10.1186/s13023-020-01379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251883PMC
May 2020

POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene.

Neurol Neurochir Pol 2019 2;53(5):369-376. Epub 2019 Oct 2.

Clinic of Pediatric and Adolescent Medicine, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 12109 Prague, Czech Republic.

Introduction And Aim Of The Study: White matter disorders represent a spectrum of neurological diseases frequently associated with an unfavourable prognosis and a delay in diagnostics. We report the broad phenotypic spectrum of a rare hypomyelinating leukodystrophy and three novel mutations. Further, we aim to explore the role of the combined clinical and neuroimaging diagnostic approach in the era of whole exome sequencing.

Materials And Methods: We present a clinical, neuroimaging and molecular-genetic characterisation of four patients from three families suffering from a rare genetic leukoencephalopathy. Two severely affected siblings (P1, P2) manifested a profound developmental delay, cerebellar symptomatology, microcephaly, failure to thrive, short stature and delayed teeth eruption with oligodontia. The other two patients (P3, P4), on the contrary, suffer from substantially less serious impairment with mild to moderate developmental delay and cerebellar symptomatology, delayed teeth eruption, or well-manageable epilepsy. In all four patients, magnetic resonance revealed cerebellar atrophy and supratentorial hypomyelination with T2-weight hypointensities in the areas of the ventrolateral thalamic nuclei, corticospinal tract and the dentate nuclei.

Results: Using whole-exome sequencing in P1, P2 and P3, and targeted sequencing in P4, pathogenic variants were disclosed in POLR3B, a gene encoding one of 17 subunits of DNA-dependent RNA polymerase III - all patients were compound heterozygotes for point mutations. Three novel mutations c.727A>G (p.Met243Val) and c.2669G>A (p.Arg890His) (P1, P2), and c.1495G>A (p.Met499Val) (P3) were found. Magnetic resonance revealed the characteristic radiological pattern of POLR3-leukodystrophies in our patients.

Conclusion And Clinical Implications: The diagnosis of POLR3-associated leukodystrophies can be significantly accelerated using the combined clinical and neuroradiological recognition pattern. Therefore, it is of crucial importance to raise the awareness of this rare disorder among clinicians. Molecular-genetic analyses are indispensable for a swift diagnosis confirmation in cases of clear clinical suspicion, and for diagnostic search in patients with less pronounced symptomatology. They represent an invaluable tool for unravelling the complex genetic background of heritable white matter disorders.
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http://dx.doi.org/10.5603/PJNNS.a2019.0042DOI Listing
November 2019

Peripapillary microcirculation in Leber hereditary optic neuropathy.

Acta Ophthalmol 2019 Feb 26;97(1):e71-e76. Epub 2018 Sep 26.

Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Purpose: In this prospective observational comparative case series, we aimed to study the peripapillary capillary network with spectral-domain optical coherence tomography angiography (OCT-A) in Leber hereditary optic neuropathy (LHON).

Methods: Twelve eyes of six individuals, of these three males (five eyes) after clinical onset of visual impairment were imaged by OCT-A with scans centred on optic discs. Control group consisted of 6 eyes with no visual impairment.

Results: The three affected individuals lost vision 6 years (at age 22 years), 2 years and 3 months (at age 26 years) and 1 year and 2 months (at age 30 years) prior to OCT-A examination. All five affected eyes had alterations in density of the radial peripapillary microvascular network at the level of retinal nerve fibre layer, including an eye of a patient treated with idebenone that underwent almost full recovery (best corrected visual acuity 0.87). Interestingly, the other eye showed normal ocular findings 14 months after onset. Results of OCT-A examination in this eye were unfortunately inconclusive due to a delineation error. At the level of the ganglion cell layer differences could be also noted, but only in two severely affected individuals. There were no differences between unaffected mutation carriers and control eyes.

Conclusion: Optical coherence tomography angiography scans confirmed that the peripapillary microvascular network is highly abnormal in eyes manifesting visual impairment due to LHON. These findings support the hypothesis that microangiopathy contributes to the development of vision loss in this mitochondrial disorder.
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http://dx.doi.org/10.1111/aos.13817DOI Listing
February 2019

Multislice CT angiographic reconstruction of marginal artery of Drummond as collateral to occluded superior mesenteric artery.

Am Heart Hosp J 2006 ;4(4):290-1

Division of Cardiovascular Medicine, University of Wisconsin Hospital and Clinics, Madison WI 53792, USA.

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http://dx.doi.org/10.1111/j.1541-9215.2006.04931.xDOI Listing
May 2007

Uptake of technetium 99m HDP in cardiac amyloidosis.

Int J Cardiovasc Imaging 2003 Jun;19(3):225-7

Section of Cardiology, William S. Middleton VAMC, USA.

We present a report and a brief summary of literature focused on a patient with suspected cardiac amyloidosis from transthoracic echocardiography and tc-99m HDP scintigraphy. Imaging demonstrated significantly increased uptake of the bone tracer within the myocardium in comparison to the highest skeletal uptake. Literature described several cases of abnormal myocardial uptake of various imaging tracers in various disease states.
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http://dx.doi.org/10.1023/a:1023608115278DOI Listing
June 2003

Adenosine myocardial perfusion single photon emission computed tomographic stress testing 24-72 h after uncomplicated myocardial infarction.

Int J Cardiovasc Imaging 2002 Aug;18(4):269-72

East Carolina University, Greenville, NC, USA.

Safety of performing adenosine myocardial perfusion stress testing as early as 24 h after acute uncomplicated myocardial infarction is not known. We evaluated 31(14 females and 17 males, average age 72, range 46-89 years) consecutive patients with uncomplicated myocardial infarction, who underwent adenosine myocardial perfusion stress imaging, 24-72 h after infarction for risk stratification. Adenosine was infused at a rate of 140 microg/kg/min for 6 min. Twenty patients were presented with non-ST-elevation myocardial infarction. Eleven patients were admitted with acute ST-elevation myocardial infarction. Patients were monitored for signs of complication during and immediately after the stress test. The average time from admission to performance of stress tests was 51 +/- 19 h, ranging from the minimum of 24 h to maximum 72 h. No complications related to adenosine infusion were detected. In conclusion, our data suggest that a further large study of early adenosine myocardial perfusion SPECT imaging may be safe in a carefully selected group of patients after uncomplicated myocardial infarction.
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http://dx.doi.org/10.1023/a:1015525311510DOI Listing
August 2002
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