NeurometPlus

Incidence

Very rare condition. Only 6 cases have been reported. Autosomal recessive transmission.

Clinical Characteristics

Tetrahydrobiopterin (BH4) cofactor is essential for various processes and is present in probably every cell or tissue of higher organisms. BH4 is required for various enzyme activities. The de novo biosynthesis pathway of BH4 from GTP involves GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, and sepiapterin reductase. The enzymes that depend on BH4 are the phenylalanine, tyrosine, and tryptophan hydroxylases. In regard to human disease, BH4 deficiency due to autosomal recessive mutations in all enzymes except sepiapterin reductase have been described as a cause of hyperphenylalaninemia. Furthermore, several neurological diseases including Dopa-responsive-dystonia (DRD), but also Alzheimer disease, Parkinson disease, autism, and depression were suggested as a consequence of limited cofactor availability. Patients with autosomal recessive BH4 deficiencies present mostly with progressive neurological deterioration regardless of the different enzyme defects. The clinical manifestation is variable but common symptoms are mental retardation, convulsions, disturbance of tone and posture, abnormal movements, hypersalivation, swallowing difficulties, temperature instability, and oculogyric crises. These patients can be detected through neonatal screening for phenylketonuria (PKU) due to abnormally high levels of phenylalanine in blood. However, autosomal recessive deficiency of sepiapterin reductase leads to BH4 and neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.
Clinical features of four patients with SR deficiency include spasticity, dystonia, microcephaly, hypersalivation, hypotonia of the trunk, hypertonia of the limbs, tremor, oculogyric crises, cortical atrophy, and progressive psychomotor retardation. The first two patients were diagnosed at the age of 5 and 10 years and they both responded to L-Dopa/Carbidopa (1-2 mg/kg/d) and 5-hydroxytryptophan (5-6 mg/kg/d). Due to the late diagnosis and thus probably irreversible brain damage a trial with BH4 in one patient was not successful. The third patient was diagnosed as SR-deficient at the age of 25 years, however, the diagnosis at the age of two years was cerebral palsy presenting with diurnal dystonia and hypersomnolence. Although this patient improved on L-Dopa and 5-hydroxytryptophan, initially she also did not tolerate the therapy. The fourth recently diagnosed patient from Heidelberg is like the first two of Turkish origin and diagnosed at the age of 8 years. He is currently on L-Dopa/Carbidopa (6 mg/kg/d). Blau et al. (1998) reported a patient who was 14-year-old adolescent male born to consanguineous parents of Turkish origin. He presented with psychomotor retardation, spasticity, dystonia, microcephaly, and growth retardation. Then in 1999, he reported another patient, a 9-year-old boy born of unrelated parents of Turkish origin. He presented with progressive psychomotor retardation, spasticity, tremor, ataxia, dystonic posturing and falls (initially misinterpreted as epileptic seizures), depressive and aggressive behavior, and oculogyric crises. There were also marked diurnal fluctuations. Administration of L-dopa resulted in clinical improvement. Bonafe et al. (2001) reported 2 patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. They presented with normal urinary pterins and without hyperphenylalaninemia. Studies of skin fibroblasts revealed inactive sepiapterin reductase, the enzyme catalyzing the final 2-step reaction in the biosynthesis of tetrahydrobiopterin (BH4). The authors suggested that autosomal recessive deficiency of sepiapterin reductase leads to BH4 and neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria. Other patient reported is 26-year-old woman with a mild form of dopa-responsive dystonia. Sepiapterin reductase activity was significantly reduced compared to controls (approximately 50%) and western blot analysis showed reduced protein quantities (approximately 39% of normal). Biopterin concentration was also reduced. The patient had walked on tiptoes as a child, suggesting fixed pes equinovarus. At age 15 years, she noticed abnormal movements of the fourth and fifth digits of the left hand; at age 19 years, she developed gait abnormalities with internal rotation, adduction, and extension of the left leg; and at age 23 years, she had dystonic movements and tremor. In 2002, a 27 year-old woman presenting with the clinical picture characterized by hypersomnolence, mild psychomotor retardation, dystonia, oculomotor apraxia, weakness, and striking diurnal variations of symptoms was reported and found to be sepiapterin reductase (SR)-deficient by investigations of pterins in cytokine stimulated fibroblasts. There was no detectable SR activity in the non-stimulated fibroblasts and mutation analysis revealed a homozygous Arg to Gly exchange at codon 150 (R150G). This was another case found with SR deficiency characterized by a severe monoamine neurotransmitters deficiency without hyperphenylalaninemia. The diagnosis was made using CSF neurotransmitters metabolites in conjunction with the fibroblasts assay for neopterin and biopterin and SR activity. Finally, SR inactivity was confirmed by mutations analysis. This case further illustrates the importance of systematic investigations (CSF) in patients with suspected impairment of monoamine neurotransmitter biosynthesis.

Precipitants

None

Provocation Tests

None

Diagnostic Procedures

The diagnosis is made using CSF neurotransmitters metabolites in conjunction with the fibroblasts assay for neopterin and biopterin and SR activity. Finally, SR inactivity can be confirmed by mutations analysis.