Autosomal recessive GTP cyclohydrolase I deficiency without hyperphenylalaninemia: Evidence of a phenotypic continuum between dominant and recessive forms

Horvath, Gabriella; Stöckler‐Ipsiroglu, Sylvia; Salvarinova-Zivkovic, Ramona; Lillquist, Yolanda; Connolly, Mary; Hyland, Keith; Blau, Nenad; Rupar, Tony; Waters, Paula J.

doi:10.1016/j.ymgme.2008.01.003

Cited by 42 publications

(45 citation statements)

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“…The dominant form, with mutation in only one of the two alleles for GTP cyclohydrolase I, causes dopa-responsive dystonia (OMIM 128230), characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of levodopa. Patients with the recessive form have mutations in both alleles for GTP cyclohydrolase I and are usually detected because of elevated phenylalanine on newborn screening, although there are exceptions (Horvath et al 2008). Patients present with developmental delays and neurological dysfunction with trunk hypotonia, hypertonia of the extremities, abnormal movements, tremors, convulsions, and sometimes autonomic dysfunction.…”

Section: Clinical Presentationmentioning

confidence: 99%

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Disorders of biopterin metabolism

Longo

2009

J of Inher Metab Disea

131

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Defects in the metabolism or regeneration of tetrahydrobiopterin (BH4) were initially discovered in patients with hyperphenylalaninaemia who had progressive neurological deterioration despite optimal metabolic control (malignant hyperphenylalaninaemia). BH4 is an essential cofactor not only for phenylalanine hydroxylase, but also for tyrosine and two tryptophan hydroxylases, three nitric oxide synthases, and glyceryl-ether monooxygenase. Defective activity of tyrosine and tryptophan hydroxylases explains the neurological deterioration in patients with BH4 deficiency with progressive mental and physical retardation, central hypotonia and peripheral spasticity, seizures and microcephaly. Five separate genetic conditions affect BH4 synthesis or regeneration: deficiency of GTP cyclohydrolase I, 6-pyruvoyl tetrahydropterin synthase, sepiapterin reductase, dihydropteridine reductase (DHPR) and pterin-4alpha-carbinolamine dehydratase. Only the latter of these conditions is relatively benign and is associated with transient hyperphenylalaninaemia. All these conditions can be identified in newborns by an elevated phenylalanine, with the exception of sepiapterin reductase and the dominant form of GTP cyclohydrolase I deficiency that results in biopterin deficiency/insufficiency only in the brain. Diagnosis relies on the measurement of pterin metabolites in urine, dihydropteridine reductase in blood spots, neurotransmitters and pterins in the CSF and on the demonstration of reduced enzyme activity (red blood cells or fibroblasts) or causative mutations in the relative genes. The outcome of BH4 deficiency is no longer malignant if therapy is promptly initiated to reduce plasma phenylalanine levels and replace missing neurotransmitters. This is accomplished by a special diet and/or BH4 supplements and administration of L-dopa, carbidopa, 5-hydroxytryptophan, and, in certain cases, a MAO-B inhibitor. Patients with DHPR deficiency also require folinic acid supplements, since DHPR may help in maintaining folate in the tetrahydro form. Several patients with BH4 deficiency treated since the newborn period have reached adult age with good outcome.

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Section: Clinical Presentationmentioning

confidence: 99%

“…There are patients, however, in whom phenylalanine levels can be either normal or minimally elevated at birth and clinical suspicion should remain for patients presenting with characteristic neurological symptoms (Horvath et al 2008). Patients with the dominant form of GTP cyclohydrolase I deficiency have normal plasma phenylalanine levels.…”

Section: Diagnosismentioning

confidence: 99%

Disorders of biopterin metabolism

Longo

2009

J of Inher Metab Disea

131

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“…The severity of the phenotype is variable. A phenotypic continuum has been proposed for GTPCH deficiency (Horvath et al 2008) that can also be applied for the other disorders of monoamine synthesis. Patients can show a severe phenotype with onset of symptoms in early infancy and minimal developmental progress; an intermediate phenotype with delayed or even normal early developmental progress and with variable onset ranging from infancy, childhood to later in life; and a mild phenotype with onset in infancy (Table 3).…”

Section: Clinical Manifestations Of the Disorders Of Monoamine Synthesismentioning

confidence: 99%

“…In the dominantly inherited form of GTPCH deficiency, cognition is intact. Patients with intermediate phenotypes may have borderline or normal cognition (Giovanniello et al 2007;Hoffmann et al 2003;Horvath et al 2008;Sedel et al 2008;Swoboda et al 1999). It is thought that the early effects of monoamine deficiency in the developing brain may account for the cognitive deficits.…”

Section: Cognitive and Behavioural Manifestationsmentioning

confidence: 99%

“…At times this poor response appears to be related to poor tolerance to the medications, such as in the case of AADC deficiency, where drug induced dyskinesias were noted in almost half of the cases (Pons et al 2004). Favourable response is also seen in patients with severe phenotypes and in general in intermediate and mild phenotypes, especially in the dominantly inherited form of GTPCH deficiency, where low doses of L-dopa provide marked sustained favourable response to L-dopa (Horvath et al 2008;Segawa et al 2003). In DBH deficiency, L-threo-3,4-dihydroxyphenylserine results in a dramatic increase in blood pressure and relief of postural symptoms (Senard and Rouet 2006).…”

Section: Treatmentmentioning

confidence: 99%

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The phenotypic spectrum of paediatric neurotransmitter diseases and infantile parkinsonism

Pons

2008

J of Inher Metab Disea

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Paediatric neurotransmitter diseases are a group of inherited disorders attributable to a disturbance of neurotransmitter metabolism. The monoamines, catecholamines and serotonin, also called biogenic amines, are neurotransmitters with multiple roles including psychomotor function, hormone secretion, cardiovascular, respiratory and gastrointestinal control, sleep mechanisms, body temperature and pain. Given the multiple functions of monoamines, disorders of their metabolism comprise a wide spectrum of manifestations, with motor dysfunction being the most prominent clinical feature. The severity of the clinical manifestations ranges from mild to severe. Patients with severe and intermediate phenotypes may present with infantile parkinsonism that differs in a number of aspects from the parkinsonism in nigrostriatal degeneration. Analysis of monoamine metabolites and pterins in spinal fluid assists in the diagnosis of these disorders. Treatment options include tetrahydrobiopterin supplementation, L: -dopa, 5-hydroxytryptophan, and medications that potentiate monoamine transmission. Response to treatment is variable.

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