Novel mutation of methylmalonyl-CoA mutase gene in a Thai infant with methylmalonic acidemia (mut0).

Isolated methylmalonic acidemia is found in patients with mutations in the MUT gene causing partial methylmalonyl CoA mutase deficiency, mut-, or complete methylmalonyl CoA mutase deficiency, mut0. Most mut0 patients have an earlier and more severe presentation than the other groups such as mut- and cbl defect. We report a 6-month-old Thai male presenting with wide-anion gap metabolic acidosis after acute lower respiratory infection. Urine organic acids analysis demonstrated excretions of methylmalonic acid and methylcitrate, consistent with methylmalonic acidemia. He was then started on low protein diet with an appropriate metabolic formula, L-carnitine (100 mg/kg/day), and oral vitamin B12 (1 mg/day). He had only one single metabolic episode at 2 years of age. At present, he is doing well with normal growth and development. His methylmalonyl-CoA mutase activity was undetectable compatible with mut0. He was found to be homozygous for a novel IVS11-2A>G mutation causing two aberrantly spliced transcripts. The identified mutation and enzyme activity of this patient should cause severe phenotype, although, our patient has milder clinical manifestations. Therefore we hypothesize that there are other factors that may determine the clinical phenotype of mutase deficiency in the present case.

Clinical and molecular characterization of an extended family with Fabry disease.

OBJECTIVE: To characterize clinical manifestations, biochemical changes, mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA), and functional capability of mutant protein. MATERIAL AND METHOD: Seventeen subjects from a family with a newly diagnosed patient with Fabry disease were enrolled in the present study. In each individual, clinical history, physical examination, leukocyte enzyme activity of alpha-Gal A, and mutation analysis were performed. Those with a mutation were further investigated by ophthalmological and audiological evaluations, electrocardiography, echocardiogram, urinalysis, and blood tests to determine renal insufficiency. Expression study of the mutant protein was performed using a Pichia pastoris expression system. RESULTS: Four affected males and five symptomatic female carriers were identified. Clinical manifestations included severe neuropathic pain, acroparesthesia, hypo-/hyper-hidrosis, frequent syncope, ischemic stroke, cardiac hypertrophy, corneal dystrophy and cart-wheel cataract, high frequency sensorineural hearing loss, periorbital edema and subcutaneous edema over hands and interphalangeal joints. None had angiokeratoma or renal symptoms. The authors identified a novel mutation, p.L106R, in the GLA gene. Recombinant expression of the mutant protein gave little or no enzyme activity compared to the normal protein. CONCLUSION: There were intrafamilial clinical variabilities, but consistent findings of the absence of angiokeratoma and renal symptoms, which could represent a unique feature of this particular mutation.

The molecular basis of mucopolysaccharidosis type I in two Thai patients.

Two Thai patients diagnosed with Hurler syndrome (mucopolysaccharidosis type 1, MPS I) were found to have no detectable alpha-iduronidase (E.C. 3.2.1.76) activity in leukocytes, while normal Thai children all had significant activity, with a mean of 135 +/- 30 nmol/mg/18h. One patient was heterozygous for A75T (311G>A) and S633L (1986C>T) mutation, previously reported to cause MPS I, together with 9 other heterozygous polymorphisms also found in normal controls. The other patient had the previously described frameshift mutation 252insert C and a new nonsense mutation E299X (983G>T).