Currently there are 91 treatable
inborn errors of metabolism that cause intellectual developmental disorders. Cerebral
creatine deficiencies (CDD) comprise three of these:
arginine: glycine amidinotransferase [AGAT],
guanidinoacetate methyltransferase [GAMT], and
X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral
creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent
speech delay,
autism,
epilepsy, extrapyramidal
movement disorders, and signal changes in the globus pallidus. Patients with
GAMT deficiency exhibit the most severe clinical spectrum.
Myopathy is a distinct feature in
AGAT deficiency.
Guanidinoacetate (GAA) is the immediate product in the
creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for
AGAT deficiency, while high GAA concentrations are characteristic markers for
GAMT deficiency. An elevated ratio of urinary
creatine /
creatinine excretion serves as a diagnostic marker in males with
SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose
creatine-monohydrate for all three CDD.
Guanidinoacetate-reducing strategies (high-dose
ornithine,
arginine-restricted diet) are additionally employed in
GAMT deficiency. Supplementation of substrates for intracerebral
creatine synthesis (
arginine,
glycine) has been used additionally to treat
SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and
GAMT deficiency suggest a potential benefit of newborn screening for these disorders.