BH4 deficiency identified in 2 patients with severe neurological phenotype followed at the phenylketonuria clinic in Pernambuco

*Correspondence: [e-mail].

Abstract

Case Presentation: Case 1: MHAS, 2 years old, daughter of consanguineous parents, followed at the phenylketonuria (PKU) outpatient clinic since the first trimester of life, after the heel prick test demonstrated phenylnalanine (FAL=16.9 mg/dL) and confirmatory test (FAL= 13.4 mg/dL). She showed signs of global developmental delay and hypotonia, even on adequate dietary treatment. During hospitalization, for 1 year and 8 months, due to the severe neurological condition, a genetic panel was collected to investigate tetrahydrobiopterin (BH4) deficiency, which showed the presence of a homozygous pathogenic variant in the PTS gene. Treatment with Sapropterin dihydrochloride and neurotransmitter replacement was initiated, with significant improvement in hypotonia, movement disorder, hypersalivation and nutritional status. Case 2: KWPS, 1 year old, daughter of consanguineous parents, initiated follow-up at the PKU clinic at 9 months old, as the result of the heel prick test, with FAL 18.4mg/dl, was retrieved only at 8 months. A confirmatory test was performed (FAL 7.8mg/dL) and treatment with a restrictive diet was started. The patient had severe hypotonia, dysphagia and developmental delay, without significant improvement. A genetic test for BH4 mutation was performed at 11 months of age, which showed a homozygous pathogenic variant in the PTS gene, and treatment with Sapropterin dihydrochloride and neurotransmitter replacement was instituted. Despite the irregular use of medications, a partial improvement in the condition was noted.

Discussion: Hyperphenylalaninemia is mostly caused by phenylketonuria. Only 2% have a cause associated with a mutation in the genes for tetrahydrobiopterin (BH4), which is a fundamental cofactor for the metabolism of phenylalanine hydroxylase. BH4 is involved in the synthesis of neurotransmitters such as dopamine, serotonin, noradrenaline and adrenaline. Although rare, BH4 deficiencies have disease-modifying treatment (especially if instituted early), which can significantly alter patient’s quality of life, since if left untreated it can lead to developmental delay, severe hypotonia, movement disorder, dysphagia and epilepsy.

Final Comments: Although started late, as reported in both cases, treatment with Sapropterin Dihydrochloride and neurotransmitter replacement showed benefit in these patients, especially in case 1 and demonstrates the importance of screening BH4 deficiency in patients screened positively for Phenylketonuria with severe neurological condition.

Publication History

Article published online:
12 May 2025