| Disease Type / Name (OMIM) | Affected Gene | Affected Enzyme | Inheritance Pattern | Key Biochemical Features | Major Clinical Features | Prevalence / Frequency among HPA cases |
|---|---|---|---|---|---|---|
| **Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD; OMIM 233910)** | **GCH1** | GTP cyclohydrolase I (GTPCH I) | Autosomal recessive | Usually **HPA present**, but can be absent in some cases; **low neopterin and low biopterin** in DBS/urine; CSF neopterin and biopterin low (pqac-00000007, pqac-00000010, pqac-00000011, pqac-00000016) | Spectrum from **early-infantile encephalopathy** with profound disability to **dystonia-parkinsonism** and **late-onset dopa-responsive dystonia**; developmental delay/regression, hypotonia, hypertonia, movement disorder, intellectual disability; better outcomes with early treatment (pqac-00000008, pqac-00000010, pqac-00000016) | Rare among BH4 deficiencies; exact proportion not given, but much less frequent than PTPSD and DHPRD (pqac-00000002) |
| **Autosomal dominant GTP cyclohydrolase I deficiency / Segawa disease / DYT5a (AD-GTPCHD; OMIM 128230)** | **GCH1** | GTP cyclohydrolase I (GTPCH I) | Autosomal dominant | **No HPA** on NBS; urine biopterin/neopterin **low to normal**; CSF often low neopterin/biopterin (pqac-00000007, pqac-00000010, pqac-00000011) | Classic **dopa-responsive dystonia**: lower-limb dystonia, gait difficulty, **diurnal fluctuation**, later parkinsonism; usually normal early development; psychiatric symptoms reported in a minority (pqac-00000008, pqac-00000010) | Not an HPA-associated BH4 deficiency; prevalence cited as **2.96 per million** for AD-GTPCHD, though ascertainment is uncertain (pqac-00000002) |
| **6-pyruvoyl-tetrahydropterin synthase deficiency (PTPSD; OMIM 261640)** | **PTS** | 6-pyruvoyl-tetrahydropterin synthase (PTPS) | Autosomal recessive | **HPA present**; **high neopterin with low biopterin** in DBS/urine; CSF pattern consistent with upstream BH4 biosynthesis block (pqac-00000007, pqac-00000010, pqac-00000011) | Most common severe BH4 deficiency phenotype: developmental delay, hypotonia/hypertonia, epilepsy, dystonia, oculogyric crises, parkinsonism/hypokinesia, intellectual disability; irreversible injury if diagnosis/treatment delayed (pqac-00000008, pqac-00000009, pqac-00000010) | **Most frequent HPA-associated BH4 deficiency, ~54%** of BH4 deficiency cases with HPA (pqac-00000002) |
| **Q-dihydropteridine reductase deficiency / Dihydropteridine reductase deficiency (DHPRD; OMIM 261630)** | **QDPR** | q-dihydropteridine reductase (DHPR) | Autosomal recessive | **HPA present**; pterin pattern in DBS/urine **variable/inconsistent**; diagnosis relies on **reduced DHPR enzyme activity in DBS**; CSF may show elevated BH2/biopterin-related abnormalities and neurotransmitter deficiency (pqac-00000007, pqac-00000010, pqac-00000011) | Developmental delay, hypotonia/hypertonia, epilepsy, movement disorder, cognitive impairment, progressive neurologic deterioration if untreated; folate-related complications recognized (pqac-00000008, pqac-00000009) | **Second most frequent HPA-associated BH4 deficiency, ~33%** of BH4 deficiency cases with HPA (pqac-00000002) |
| **Sepiapterin reductase deficiency (SRD; OMIM 612716)** | **SPR** | Sepiapterin reductase (SR) | Autosomal recessive | Typically **no HPA**; DBS/urine biopterin and neopterin often normal; **urine sepiapterin elevated** (must be specifically requested); CSF shows elevated sepiapterin/biopterin with low neurotransmitter metabolites (pqac-00000007, pqac-00000011, pqac-00000014, pqac-00000015) | Developmental delay, speech delay/dysarthria, axial hypotonia, dystonia, ataxia, weakness, oculogyric crises, **diurnal fluctuation**, fatigue, parkinsonism, cognitive impairment; often missed by newborn screening because HPA is absent (pqac-00000010, pqac-00000014, pqac-00000015) | Not HPA-associated on NBS; nearly **60 cases** reported in literature in one 2024 case review (pqac-00000014) |
| **Pterin-4-alpha-carbinolamine dehydratase deficiency / Primapterinuria (PCDD; OMIM 264070)** | **PCBD1** | Pterin-4-alpha-carbinolamine dehydratase (PCD) | Autosomal recessive | **HPA present**; **primapterin elevated in urine** (specific hallmark), with biopterin low-normal and neopterin normal-high; primapterin not reliably detected in DBS (pqac-00000007, pqac-00000010, pqac-00000011) | Often **asymptomatic or very mild**; transient tone abnormalities, slight tremor, mild motor delay reported; patients should also be screened for **hypomagnesemia** and **HNF1A-like MODY3 diabetes** later in life (pqac-00000008, pqac-00000010) | Rare; included among HPA-associated BH4 deficiencies but far less common than PTPSD or DHPRD; exact percentage not specified (pqac-00000002) |


*Table: This table summarizes the six recognized tetrahydrobiopterin deficiency disorders, including their genes, enzymes, inheritance, biochemical signatures, major clinical manifestations, and relative frequency. It is useful for distinguishing HPA-associated from non-HPA BH4 disorders and for guiding diagnosis and disease classification.*