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  • 1
    Online Resource
    Online Resource
    Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients
    Wiley ; 2021
    In:  Journal of Inherited Metabolic Disease Vol. 44, No. 4 ( 2021-07), p. 1070-1082
    Details
    In: Journal of Inherited Metabolic Disease, Wiley, Vol. 44, No. 4 ( 2021-07), p. 1070-1082
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0141-8955 , 1573-2665
    URL: Issue
    URL: Article
    DOI: 10.1002/jimd.v44.4
    DOI: 10.1002/jimd.12360
    RVK:
    YC 6270
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2006875-X
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  • 2
    Online Resource
    Online Resource
    Four novel PDHA1 mutations in pyruvate dehydrogenase deficiency
    Wiley ; 2009
    In:  Journal of Inherited Metabolic Disease Vol. 32, No. S1 ( 2009-12), p. 235-239
    Details
    In: Journal of Inherited Metabolic Disease, Wiley, Vol. 32, No. S1 ( 2009-12), p. 235-239
    Abstract: The pyruvate dehydrogenase (PDH) complex is a mitochondrial multienzyme that catalyses the irreversible oxidative decarboxylation of pyruvate to acetyl‐CoA. We report four novel PDHA1 mutations in patients with pyruvate dehydrogenase deficiency. Analysis of PDH activity showed decreased activity in fibroblasts from all four patients, around 16–52% of mean control, similar to what has been found in previous studies. Two of the mutations were missense mutations: c.616G 〉 A (p.Glu206Lys) and c.457A 〉 G (p.Met153Val), one was a 3 bp in‐frame deletion: c.429_431delAGG (p.Gly143del), and one was a 65 bp duplication: c.900–6_958dup65. cDNA analysis of the 65 bp duplication showed a small amount of normal transcript in addition to the transcript corresponding to the duplication. The small amount of normal transcript likely explains the survival of the patient, who was a boy. The duplication and one of the missense mutations were associated with decreased amounts of E 1 α And E 1 β protein on western blot analysis, whereas the other two mutations were associated with normal amounts. This study adds four novel mutations to the around 90 reported mutations in PDHA1 (HGMD PDHA1 mutation database). The phenotypes of patients with PDH deficiency have been divided into three groups: a neonatal form with severe lactic acidosis, a form observed only in males and characterized by episodes of ataxia with relapses associated with hyperlactataemia, and an infantile form with hypotonia, lethargy, onset of seizures or dystonia, psychomotor retardation, in some cases Leigh‐like lesions and mild to moderate hyperlactataemia. The four patients reported here all belong to the latter group, which is the largest.
    Type of Medium: Online Resource
    ISSN: 0141-8955 , 1573-2665
    URL: Article
    DOI: 10.1007/s10545-009-1179-8
    RVK:
    YC 6270
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2006875-X
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  • 3
    Online Resource
    Online Resource
    Assessment of intellectual impairment, health‐related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry
    Wiley ; 2021
    In:  Journal of Inherited Metabolic Disease Vol. 44, No. 6 ( 2021-11), p. 1489-1502
    Details
    In: Journal of Inherited Metabolic Disease, Wiley, Vol. 44, No. 6 ( 2021-11), p. 1489-1502
    Abstract: 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 4 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 4 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 4 deficiencies and primary neurotransmitter‐related disorders and (b) previously underreported behavioral traits.
    Type of Medium: Online Resource
    ISSN: 0141-8955 , 1573-2665
    URL: Issue
    URL: Article
    DOI: 10.1002/jimd.v44.6
    DOI: 10.1002/jimd.12416
    RVK:
    YC 6270
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2006875-X
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  • 4
    Online Resource
    Online Resource
    The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency
    Wiley ; 2024
    In:  Journal of Inherited Metabolic Disease
    Details
    In: Journal of Inherited Metabolic Disease, Wiley
    Abstract: The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long‐term follow‐up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8–33.4 years) showed a diversifying course in follow‐up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.
    Type of Medium: Online Resource
    ISSN: 0141-8955 , 1573-2665
    URL: Article
    DOI: 10.1002/jimd.12723
    RVK:
    YC 6270
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2006875-X
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