Creatine deficiency syndrome. A treatable myopathy due to arginine-glycine amidinotransferase (AGAT) deficiency.

We report two sisters, aged 11 and 6years, with AGAT deficiency syndrome (OMIM 612718) which is the least common creatine deficiency syndrome. They were born full-term to consanguineous parents and had moderate developmental delay. Examination showed an important language delay, a progressive proximal muscular weakness in the lower limbs with Gowers sign and myopathic electromyography. Investigations revealed undetectable guanidinoacetate and low level of creatine in plasma and urine, characteristic findings of AGAT deficiency syndrome. Brain magnetic resonance spectroscopy showed a markedly reduced level of creatine. Guanidinoacetate methyltransferase (GATM) gene sequencing revealed a homozygous missense mutation in exon 4:c.608A>C, (p.Tyr203Ser). Thirteen months after beginning the treatment with oral creatine monohydrate 200mg/kg/day, then 400mg/kg/day, there was a dramatic improvement in muscle strength with Gowers sign disappearance in both patients, and a mild improvement in language and cognitive functions. AGAT deficiency syndrome should be considered in all patients with language retardation and cognitive impairment associated to a myopathy of unknown etiology such that early diagnosis must lead to creatine supplementation to cure the myopathy and improve language and cognitive function.

Novel mutations in pyridoxine-dependent epilepsy.

PURPOSE: Pyridoxine-Dependent Epilepsy (PDE) is a rare autosomal recessive disease with neonatal seizures resistant to conventional anti-epileptic drugs. This metabolic disease has to be diagnosed early and treated to improve outcome. We report on two new mutations that open new prenatal prospects and suggest a new diagnostic procedure. CASE REPORT: We describe PDE in a neonate carrying two novel mutations in the ALDH7A1 gene: c.[852_856delCTTAG] + [1230C > A]; p.[(Phe410Leu)] + p.[(Leu285CysfsX26)]. This case also illustrates that diagnosis could have been made without any pyridoxine withdrawal, thanks to the measurement of biomarkers. The patient was successfully treated with pyridoxine supplementation and currently shows normal neurological development.

Use of a long-chain triglyceride-restricted/medium-chain triglyceride-supplemented diet in a case of malonyl-CoA decarboxylase deficiency with cardiomyopathy.

Malonyl coenzyme A (CoA) decarboxylase (EC 4.1.1.9, MCD) deficiency, or malonic aciduria, is a rare inborn error of metabolism characterised by a variable phenotype of developmental delay, seizures, cardiomyopathy and acidosis. There is no consensus for dietary treatment in this condition. This case describes the effect of a long-chain triglyceride (LCT)-restricted/medium-chain triglyceride (MCT)-supplemented diet upon the progress of an affected child. A full-term Asian girl of birth weight 3590 g was screened for malonic aciduria after birth due to a positive family history. She had elevated urine malonic and methylmalonic acids and was presumably homozygous for a deleterious mutation in the MLYCD gene. Her echocardiography showed mild cardiomyopathy at 0.5 months of age, but heart function was good. She was treated with carnitine 100 mg/kg per day and continued a high-energy formula feed, as her growth was slow. At 3 months of age, echocardiography showed deteriorating cardiac function with a fractional shortening of 18%. She started an angiotensin-converting enzyme (ACE) inhibitor (Captopril). Over the next few months, her diet was altered to comprise 1.9% energy from LCT, 25% from MCT and the remainder carbohydrate. Cardiac function improved and was optimal at 23 months of age, with a fractional shortening of 28% and good systolic function. During a period of low MCT intake, her cardiac function was noted to deteriorate. This reversed and stabilised following reinstatement of the diet. This case of malonic aciduria with cardiomyopathy demonstrates improvement in cardiac function attributable to LCT-restricted/MCT-supplemented diet.

Arginine supplementation in four patients with X-linked creatine transporter defect.

BACKGROUND: Treatment with oral creatine monohydrate has not shown efficacy in patients with creatine transporter deficiency (CRTR-D). Another therapeutic option proposed is L-arginine, the substrate for the enzyme L-arginine:glycine amidinotransferase (AGAT). We evaluate clinical characteristics and cerebral creatine replenishment after L-arginine therapy in four patients with CRTR-D. PATIENTS AND METHODS: Four boys with genetically confirmed diagnosis of CRTR-D (ages 9-16 years) were supplemented with L-arginine (0.4 g/kg per day) for a period of 9 months. Treatment efficacy was evaluated by clinical and neuropsychological assessment and determination of creatine signals by brain proton magnetic resonance spectroscopy ((1)H-MRS). RESULTS: Epileptic seizures remained well controlled with antiepileptic drugs in three cases, both before and after L-arginine supplementation. Vineland Adaptive Behaviour Scale did not show any change in communication, daily living skills, socialization or motor skills, and a lack of improvement in brain (1)H-MRS follow-up was observed. L-Arginine was discontinued at the end of the observation period. CONCLUSIONS: Nine months of L-arginine supplementation did not show effectiveness in the four patients affected with CRTR-D in this protocol.

GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis.

BACKGROUND: Guanidinoactetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine synthesis. The authors analyzed clinical, biochemical, and molecular findings in 27 patients. METHODS: The authors collected data from questionnaires and literature reports. A score including degree of intellectual disability, epileptic seizures, and movement disorder was developed and used to classify clinical phenotype as severe, moderate, or mild. Score and biochemical data were assessed before and during treatment with oral creatine substitution alone or with additional dietary arginine restriction and ornithine supplementation. RESULTS: Intellectual disability, epileptic seizures, guanidinoacetate accumulation in body fluids, and deficiency of brain creatine were common in all 27 patients. Twelve patients had severe, 12 patients had moderate, and three patients had mild clinical phenotype. Twenty-one of 27 (78%) patients had severe intellectual disability (estimated IQ 20 to 34). There was no obvious correlation between severity of the clinical phenotype, guanidinoacetate accumulation in body fluids, and GAMT mutations. Treatment resulted in almost normalized cerebral creatine levels, reduced guanidinoacetate accumulation, and in improvement of epilepsy and movement disorder, whereas the degree of intellectual disability remained unchanged. CONCLUSION: Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.

Enteral inulin does not affect epithelial gene expression and cell turnover within the ileoanal pouch.

PURPOSE: This study evaluates the effects of enteral inulin on ileoanal pouch functioning by studying epithelial gene expression, cell turnover, and mucosal morphology. METHODS: Twenty patients with an ileoanal pouch received 24 g of inulin daily for three weeks, then a four-week wash-out period, and a placebo for three weeks. In this randomized, double-blind, crossover study, biopsy specimens of pouch mucosa were taken after each test period. Mucosal morphology, inflammation, epithelial proliferation, and cell death were assessed histologically. Expressions of proapoptotic and antiapoptotic regulators, intestinal fatty acid-binding protein, and mucin were quantified by Western blotting or enzyme-linked immunosorbent assay. The number of intestinal fatty acid-binding protein expressing cells was histologically assessed and a high iron diamine/Alcian blue staining was performed to discriminate between sulfated and nonsulfated acidic mucins. RESULTS: Inulin supplementation neither altered mucosal morphology nor influenced inflammation, epithelial cell proliferation, or cell death. The ratio between the proapoptotic and antiapoptotic regulators did not change after inulin supplementation. The number of intestinal fatty acid-binding protein-producing enterocytes and the intestinal fatty acid-binding protein expression level increased after inulin treatment, but did not reach statistical significance. The intestinal fatty acidbinding protein expression level correlated with the Pouchitis Disease Activity Index, which was at the brink of significance (P = 0.06). Mucin expression and the ratio between sulfated and nonsulfated acidic mucins were not altered by inulin supplementation. CONCLUSION: In this prospective study, inulin supplementation did not significantly alter pouch mucosal functioning because neither epithelial homeostasis nor epithelial gene expression was significantly altered by enteral inulin.