Dr Mary D King at Department of Neurology, Children's University Hospital, Temple Street, Dublin 1, Ireland. E-mail: firstname.lastname@example.org
Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by early-onset learning disability and epilepsy in most affected children. Severe expressive language delay is a constant feature even in the mildest clinical phenotypes. We report the clinical, biochemical, imaging, and treatment data of two female siblings (18y and 13y) with an unusual phenotype of GAMT deficiency. The oldest sibling had subacute onset of a movement disorder at age 17 years, later than has been previously reported. The younger sibling had better language skills than previously described in this disorder. After treatment with creatine, arginine restriction and ornithine-supplemented diet, seizure severity and movement disorder were reduced but cognition did not improve. This report confirms that GAMT deficiency, a heterogeneous, potentially treatable disorder, detected by increased levels of guanidinoacetate in body fluids (e.g. plasma or urine) or by an abnormal creatine peak on magnetic resonance spectroscopy, should be considered in patients of any age with unexplained, apparently static learning disability and epilepsy.
Cerebral creatine deficiency syndromes include two autosomal recessive disorders of creatine synthesis, arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency, and one X-linked disorder of creatine transport.1 GAMT deficiency is the most common disorder of creatine synthesis.2 The diagnosis is made by finding accumulation of guanidinoacetate (GAA) in body fluids (GAA being the substrate to the deficient enzyme GAMT), absence of a creatine peak on magnetic resonance spectroscopy (MRS), impaired GAMT activity in lymphoblasts and fibroblasts, and mutations in the GAMT gene on chromosome 19. Serum creatinine may be low or normal.3 Early-onset learning disability* and epilepsy are constant features. Movement disorder, seen in 50% of patients, presents before 12 years.1,2,4 Severe expressive language delay is a major feature, with affected children unable to speak more than 10 words.1,2,4–7
We report two females with GAMT deficiency and atypical clinical features, one having relatively preserved expressive language, the other with late-onset movement disorder first appearing at 17 years of age. Informed consent was obtained from the father for publication of this case report.
Two female siblings (18y and 13y) were born after an uneventful pregnancy and delivery to nonconsanguineous Irish parents. The younger female is a non-identical twin, her sibling being unaffected.
Development was normal until 1 year. The patient walked at 15 months, babbled and showed signs of nonverbal communication and symbolic play, but lost these skills between 18 months and 2 years, when seizures emerged in the form of myoclonus and staring episodes. Electroencephalography (EEG) showed generalized spike and slow wave (3Hz) activity. Computed tomographic brain scan, karyotype, ammonia, lactate, carnitine, acylcarnitine, amino acids and urine organic acids were normal. Serum creatinine was 9 to 16mmol/l (normal range 20−50mmol/l).
Seizures were resistant to multiple drugs but controlled at 5 years by sodium valproate and vigabatrin. At 15 years she had severe learning disability with autistic features and impulsive behaviour. Her expressive speech was limited to fewer than 10 words. She demonstrated independence in mobility and daily self-help skills, and could follow simple commands.
At 17 years a slowing of mobility was noted, followed by twisting movements of the head and grimacing. She displayed mood change in the form of bouts of anxiety and agitation. A drug effect was considered as she was on risperidone, sodium valproate, and vigabatrin. The movements became ballistic and dystonic, affecting the face, neck, and limbs and leading to a flexed posture.
Magnetic resonance imaging (MRI) at 17 years showed increased signal in the globus pallidus bilaterally (Fig. 1) and absence of a creatine peak (Fig. 1, pretreatment). Results of biochemical testing are given in Table I. GAMT enzyme activity in cultured fibroblasts was impaired (0pmol/h/mg protein, normal range 60−243pmol/h/mg protein), confirming GAMT deficiency. GAMT gene mutation analysis showed compound heterozygosity for two mutations, a known 13 nucleotide duplication on exon 2 (c.299dup13G) that results in a frameshift and a premature stop, and a novel G to A transition on exon 4 (c.403G>A) which results in the replacement of aspartic acid by asparagine at position 135 (p.Asp135Asn). This missense variation was not detected in 210 control chromosomes. Aspartic acid 135 is highly conserved in evolution and is present in almost all GAMT species, suggesting that this mutation represents the pathogenic mutation.
Table I. Biochemical characteristics of patient 1 and patient 2
Biochemical measurements were performed using stable isotope dilution gas chromatography-mass spectrometry.14 Guanidinoacetate methyltransferase (GAMT) enzyme activity was measured according to Verhoeven et al.15 DNA mutation studies of GAMT gene were done according to Caldeira Araujo et al.13
Serum guanidinoacetate (μmol/l)
0.35−1.8 (age <15y) 1.0−3.5 (age >15y)
Urine guanidinoacetate (mmol/mol creatinine)
4−220 (age <15y ) 3–78 (age >15y)
Serum creatine (μmol/l)
6–50 (age >10y)
Urine creatine (mmol/mol creatinine)
11–244 (age >12y)
Serum creatinine (μmol/l)
GAMT enzyme activity (pmol/h/mg protein)
Treatment was started with three divided doses of creatine monohydrate at 2g/kg/day and an ornithine-supplemented and arginine-restricted diet aimed at reducing the neurotoxic levels of GAA. Natural protein intake was approximately 0.9g/kg/day with an arginine-free amino acid mixture approximately 0.7g/kg/day. Arginine intake from natural protein was 40mg/kg/day. Ornithine, arginine, other amino acids, and ammonia were monitored twice weekly when the diet was modified and at every hospital visit (6−12wks). Nine months later seizure frequency and severity of movement disorder were reduced but there was no change in cognition. MRI showed almost complete resolution of the globus pallidus lesion and appearance of the creatine peak, confirming entry of creatine into the brain (Fig. 1, posttreatment).
The sibling of patient 1 (now 13y) had delayed milestones in the first year compared with her unaffected twin. At 9 months she showed global development delay. Staring episodes with myoclonic seizures evolved at 18 months. EEG showed generalized spike and slow wave activity. The seizures ceased on sodium valproate and vigabatrin. From 2 years she showed marked hyperactivity and impulsive behaviour. She had moderate to severe learning disability but her expressive language was much better than that of her sibling. At 13 years she could speak in short sentences and made good use of syntax, pronouns, negatives, and tenses. There were no abnormal movements and she showed independence in all self-help skills.
In view of the diagnosis in her sibling, investigations for GAMT deficiency were performed. MRI at 13 years was normal but a creatine peak was absent on MRS. Biochemical markers (Table I) showed abnormalities similar to those seen in her sibling. GAMT gene mutation analysis showed the same compound heterozygous mutations as detected in her sibling’s DNA. Dietary treatment was initiated with similar MRS response.
We describe two siblings with GAMT deficiency, the first with a later onset of movement disorder, the second with less severe speech impairment, than previously reported.
A review of the clinical features of 27 previously reported cases of GAMT deficiency showed that onset of symptoms was between 3 months and 13 years and mean age at diagnosis was 12 years 4 months (range 2−29y).4 There was no correlation between the severity of the phenotype, level of GAA accumulation in body fluids, and the GAMT mutations seen. Brain MRI was normal in several cases.
A scoring system was used to assess the pretreatment clinical severity of patients with GAMT deficiency.4 The clinical features (intellectual disability, epilepsy, movement disorder) were scored with 0, 1, 2, or 3 points, increasing in severity from 0 to 3. The phenotype was severe in most, with profound learning disability and epilepsy predominating. Hyperactivity, autistic features, and self-mutilation were seen in 78%. Movement disorder was seen in 48% (always with learning disability), emerging before age 12 years in all. In the present report, patient 1 scored a severe phenotype (intellectual disability , seizures , movement disorder ) and patient 2 an intermediate phenotype (intellectual disability , seizures , movement disorder ). Patient 1 appears to have had the latest age of onset of movement disorder so far reported. This disorder should therefore be added to the list of inborn errors of metabolism which may present in adulthood.8
Patient 2 displayed less severe speech delay than previously described. Despite having difficulty initiating and maintaining conversation, she spoke in short sentences, and had an extensive vocabulary and appropriate syntax development. Severe speech delay has been described in all cases of GAMT deficiency, with patients able to speak only 10 words or fewer.1,2,4–7 A milder phenotype with near-normal non-verbal communication skills has been described.7
The mechanism of brain injury in GAMT deficiency includes depletion of creatine and accumulation of GAA. Lack of creatine shifts the kinetics of the creatine kinase reaction (ATP + Cr ↔ ADP + PCr) towards the left, producing accumulation of ATP.3 The resolution of brain lesions in the basal ganglia (globus pallidus) with creatine supplementation, reported in the literature and seen in patient 1 of this report, suggests that depletion of creatine may be important in the pathogenesis of basal ganglia lesions. However, GAA, a guanidine compound known for its neurotoxic action and epileptogenic potential,9 probably contributes to neurological injury, as movement disorder has not been reported in other disorders of creatine deficiency in which GAA levels are normal. It is likely that both creatine depletion and GAA accumulation produce the cognitive effects which, once established, appear to be irreversible with therapy.
GAMT deficiency is treated with oral creatine, ornithine supplementation, and substrate arginine restriction to reduce (by competitive inhibition) AGAT activity and thereby GAA.10 Clinical response is variable, with little improvement in cognition in most patients diagnosed after the neonatal period, although an improvement in non-verbal IQ score from 50 to 76 has been described in one child treated at 3 years 8 months.11 The biochemical response to treatment is best monitored by brain MRS, as plasma or urinary GAA is less reliable.3
Most patients with GAMT deficiency have a severe phenotype of early onset with a symptom-free prodrome in infancy, so that neonatal detection is necessary to prevent severe learning difficulties. Recently, presymptomatic disease detection in the neonatal period and apparently successful treatment have been reported, highlighting the need for pilot studies to establish the incidence of this disorder and the role of neonatal screening.12 A prevalence in unexplained learning disability of 2.7% has been reported.13 Thus, it is recommended that GAMT deficiency be considered in the evaluation of patients of any age with unexplained severe learning disability and epilepsy, whether or not movement disorder is present.