R233H mutation in patients with tyrosine hydroxylase deficiency and corresponding phenotypes: a study of four cases and literature review

Abstract

Owing to the small number of patients with tyrosine hydroxylase (TH) deficiency, no genotype-phenotype correlations have yet been identified. To investigate the genotype-phenotype correlation of R233H mutation in TH deficiency, we analyzed the clinical manifestations and treatment responses of four patients with the R233H homozygous mutation. Thirty-eight additional patients, available from the literature, known to be homozygous or heterozygous for the R233H mutation, were combined with the four cases from our hospital. Data for a total of 42 patients were retrieved. Our four patients showed clinical presentation consistent with Type A TH deficiency, and responded well to levodopa therapy, with an improvement in clinical symptoms within 1-2 weeks. In the 42 patients, 20 of 42 patients (48%) were homozygous and 22 (52%) were heterozygous for the R233H mutation. Of the 20 patients who were homozygous for the R233H mutation, a majority (80%) su fered from Type A TH deficiency. Of the 8 patients that were heterozygous for the R233H/the mutation located downstream of exon 11, 7 patients (86%) su fered from Type B TH deficiency. Of the 7 patients who were heterozygous for the R233H/nonsense mutation, 6 (86%) su fered from Type B TH deficiency. Genotype-phenotype correlation of R233H mutation was observed in TH deficiency. The homozygous R233H mutation frequently manifests as Type A TH deficiency, whereas R233H/nonsense mutation or any mutation located downstream of exon 11 manifests as Type B TH deficiency.

Tyrosine hydroxylase variants influence protein expression, cellular localization, stability, enzymatic activity and the physical interaction between tyrosine hydroxylase and GTP cyclohydrolase 1

“…27,28 Variants in the splice sites of introns of the TH gene have also been reported, 29,30 but most of the variants found in patients are missense variants. p.R233H (Dutch variant), 31,32 Note: Half-life of each protein variant as calculated by GraphPad Prism using the raw data of proteinase K digestion based on nonlinear fitting with one phase decay. Variants can be classified as stable (1-6.5 min), intermediate (0.1-1 min) and fast decay (>0.1 min) variants according to their calculated half-life.…”

“…Variants in the splice sites of introns of the TH gene have also been reported, 29,30 but most of the variants found in patients are missense variants. p.R233H (Dutch variant), 31,32 p.L236P and p.G247S are frequently found in different patients and populations, but most of the other reported variants are private 10,26,33–40 making good genotype–phenotype correlations difficult.…”

Mouse models for inherited monoamine neurotransmitter disorders

“…This TH variant is mostly associated with DRD when in homozygosity, although 20%-30% of these patients present the most severe, non-Dopa responsive form. 42,45 Various transgenic mice with TH deficiency have been described, initially independently by two laboratories, by complete knock-outs (Th-ko) which presented mid-gestational or perinatal lethality. 46,47 Rescue mutants did not fully reproduce the clinical and pathological features of TH deficiency either but they were fundamental to demonstrate the crucial role of dopamine for movement and feeding.…”

Diagnosis of autism in a rare case of tyrosine hydroxylase deficiency: a case report

“…The WES revealed the patient to be compound heterozygous for two variants in TH gene: c.698G > A; p.R233H & c.920 C > G; p.S307C (NM_199292.2 confirming a diagnosis of autosomal recessive THD. R233H transversion is the most frequently seen pathogenic variant in individuals with THD, carried by 42 patients reported thus far in the literature [ 41 ]. The S307C variant has not previously been reported to our knowledge and is a novel variant.…”