Guanidinoacetate methyltransferase deficiency identified in adults and a child with mental retardation

Abstract: Our study describes the adult clinical and biochemical spectrum of guanidinoacetate methyltransferase (GAMT) deficiency, a recently discovered inborn error of metabolism. The majority of the previous reports dealt with pediatric patients, in contrast to the present study. A total of 180 institutionalized patients with a severe mental handicap were investigated for urine and plasma uric acid and creatinine. Patients with an increased urinary uric acid/creatinine ratio and/or decreased creatinine were subjected to the analysis of guanidinoacetate (GAA). Four patients (three related and one from an unrelated family) were identified with GAMT-deficiency. A fifth patient had died before a biochemical diagnosis could be made. They all had shown a normal psychomotor development for the first year of life, after which they developed a profound mental retardation. Three out of four had convulsions and all four totally lacked the development of speech. Their GAMT activity in lymphoblasts was impaired and two novel mutations were identified: the 59 G > C and 506 G > A missense mutations. Urinary GAA was increased, but highly variable 347-1,624 mmol/mol creat (Controls <150 mmol/mol creat). In plasma and CSF the GAA levels were fairly constant at 17.3-27.0 mumol/L (Controls 1.33-3.33) and 11.0-12.4 mumol/L, respectively (Controls 0.068-0.114). GAMT deficiency in adults is associated with severe mental retardation and absence or limited speech development. Convulsions may be prominent. The nonspecific nature of the clinical findings as well as the limited availability of GAA assays and/or in vivo magnetic resonance spectroscopy of the brain may mean that many more patients remain undiagnosed in institutions for persons with mental handicaps.

Parent Summary: Caldeira Araújo et al. explored the prevalence of GAMT deficiency within a population of 180 individuals who were institutionalized (presumably in Portugal) and who displayed intellectual/developmental disabilities. The authors measured uric acid and creatinine in urine and plasma, and patients with a high urinary uric acid/creatinine ratio levels (that is, more uric acid than creatinine) or a low creatinine level then underwent an evaluation of urinary and plasma guanidinoacetic acid (GAA). High GAA levels are also suggestive of GAMT deficiency; genetic analyses were also performed. Overall, 4 patients (and a 5th potential patient who had passed away before confirmatory analyses could be performed) were identified as having GAMT deficiency, 3 of whom were from one family and the 4th being a third cousin of that family. The 5th patient was unrelated to the first 4 patients. The authors noted that while all patients had relatively normal motor development early in life, they showed a rapid decline in intellectual capacity in their 2nd year of life. More comprehensive clinical reports on the patients are also provided.

Link to article: https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.30226

PubMed:  https://pubmed.ncbi.nlm.nih.gov/15651030/

Authors: H. Caldeira Araújo, W. Smit, N.M. Verhoeven, G.S. Salomons, S. Silva, R. Vasconcelos, H. Tomás, I. Tavares de Almeida, C. Jakobs, M. Duran

Key Terms: GAMT, Clinical Study, Mutation Study, Diagnostic, Adult Patient, Pediatric Patient