Hyperphenylalaninemia, Bh4-Deficient, D

A number sign (#) is used with this entry because tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) due to pterin-4-alpha-carbinolamine dehydratase deficiency (HPABH4D) is caused by homozygous or compound heterozygous mutation in the PCBD gene (126090), which encodes an enzyme involved in the salvage pathway for BH4, on chromosome 10q22.

Description

Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (Thony et al., 1998). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (summary by Ferre et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of BH4-deficient hyperphenylalaninemia, see HPABH4A (261640).

Clinical Features

Primapterinuria, a variant form of hyperphenylalaninemia, is characterized by excretion of 7-substituted pterins in urine (Curtius et al., 1988). Patients were reported by Dhondt et al. (1987, 1988), Blaskovics and Giudici (1988), and Blau et al. (1988). Patients with primapterinuria show an increased ratio of neopterin to biopterin in the urine, excretion of subnormal levels of biopterins, and normal levels of biogenic amines in cerebrospinal fluid. In all cases, hyperphenylalaninemia was transient. Loading tests with tetrahydrobiopterin and sepiapterin suggested that 7-biopterin (primapterin) is formed by rearrangement from 6-substituted pterins (Giudici et al., 1991).

Blau et al. (1992) proposed that carbinolamine dehydratase deficiency is responsible for the findings in a female patient studied in detail. A brother showed a similar pterin pattern, had had a transient plasma phenylalanine elevation in the neonatal period, and was later clinically normal. Adler et al. (1992) independently suspected that carbinolamine dehydratase is the site of the deficiency. Furthermore, they performed kinetic experiments to verify that tetrahydroprimapterin inhibits phenylalanine hydroxylase.

Thony et al. (1998) reported 6 patients with mild hyperphenylalaninemia on neonatal screening who were found to have increased serum and urinary 7-biopterin. Ferre et al. (2014) reported follow-up of 1 of the patients (BIODEF 272) reported by Thony et al. (1998), and noted that he had developed nonautoimmune diabetes mellitus in his late teens. He was initially treated with insulin, but was later managed well on oral agents. The patient also had hypomagnesemia and hypermagnesuria.

Thony et al. (1998) reported 4 unrelated children with HPABH4D confirmed by genetic analysis. Three patients were detected by neonatal screening, whereas 1 had normal neonatal screening but developed hyperphenylalaninemia at age 1 month. All patients also showed increased urinary 7-biopterin levels. Treatment of 2 patients with BH4 resulted in decreased phenylalanine levels. All patients had normal psychomotor development between ages 2 and 6 years. Ferre et al. (2014) reported follow-up of 2 of the patients (BIODEF 329 and BIODEF 319) reported by Thony et al. (1998). One had hypomagnesemia and hypermagnesuria but did not develop diabetes mellitus, whereas the other had borderline hypomagnesemia and developed nonautoimmune diabetes mellitus at age 16 years.

Simaite et al. (2014) reported a girl from a consanguineous Turkish family who developed nonautoimmune diabetes mellitus at age 14 years. Linkage analysis and whole-genome sequencing identified a homozygous truncating mutation in the PCBD1 gene in this patient, consistent with a diagnosis of HPABH4D. However, the patient had no history of hyperphenylalaninemia, even as a newborn. By reevaluation of patients with neonatal hyperphenylalaninemia caused by PCBD1 mutations who were included in a database, they found that 3 of 7 children from 6 families developed antibody-negative diabetes mellitus with normal pancreatic morphology during puberty. Two of the 7 patients were younger than 5 years of age. Several of these patients had previously been reported by Thony et al. (1998) and Thony et al. (1998). The patients showed a good response to oral sulfonylureas or glinides. Eight family members in 4 families developed type 2 diabetes as adults; heterozygous PCBD1 mutations were confirmed in 4 of these individuals, all of whom were obese or overweight. No heterozygous mutation carriers with a normal body mass index developed type 2 diabetes. Simaite et al. (2014) suggested that patients with biallelic PCBD1 mutations be monitored for early-onset diabetes, and that even heterozygous PCBD1 mutations may increase susceptibility to type 2 diabetes when combined with other risk factors.

Inheritance

The transmission pattern of HPABH4D in the families reported by Simaite et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

Citron et al. (1993) identified mutations in the 4-alpha-carbinolamine dehydratase gene in a mildly hyperphenylalaninemic child who excreted large amounts of 7-biopterin (126090.0001; 126090.0002). In the family reported by Citron et al. (1993), no phenotypic manifestations were evident other than the presence of 7-biopterin and elevated blood levels of phenylalanine in the proband. Clinical liver function tests yielded results within the normal range.

In 6 patients with hyperphenylalaninemia with high levels of 7-biopterin, Thony et al. (1998) demonstrated homozygous mutations in the PCBD gene (see 126090.0001, 126090.0003, and 126090.0005).

Ferre et al. (2014) found that 5 previously reported PCBD1 mutations in HPABH4D patients (e.g., Q87X, 126090.0001; E27X, 126090.0006; Q98X, 126090.0005) resulted in proteolytic instability, leading to reduced FXYD2 (601814) promoter activity and increased renal magnesium loss. Cytosolic localization of PCBD1 increased when coexpressed with HNF1B (189907) mutants. The findings established PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the renal distal collecting tubule.

Animal Model

Simaite et al. (2014) found that Pcbd1 is expressed in the developing pancreas in both mouse and Xenopus embryos. Morpholino knockdown of pcbd1 in Xenopus resulted in a significant reduction in the expression of pancreatic progenitor genes, as well as reduced expression of hnf1b. The finding suggested that pcbd1 activity in the endoderm is required for proper establishment of the pancreas.

In mice, Ferre et al. (2014) found expression of Pcbd1 mostly in the distal convoluted tubule of the kidney. Pcbd1 expression increased when mice were fed a low magnesium diet, suggesting that Pcbd1 is important for renal magnesium reabsorption. In vitro studies showed that PCBD1 regulated HNF1B-mediated transcription of FXYD2, influencing active renal magnesium absorption.