A rare autosomal recessive inherited syndrome. It is characterized by xeroderma pigmentosum, mental retardation, dwarfism, hypogonadism, and neurologic abnormalities.

Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.

Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.