Clinical characteristics: The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs.

1. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder.

2. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders.

3. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.

Diagnosis/testing: The diagnosis of a CDD is established in a proband with suggestive findings and biallelic pathogenic variants in GAMT or GATM or a hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular genetic testing.

Management: Treatment of manifestations: GAMT deficiency and AGAT deficiency are treated with oral creatine monohydrate to replenish cerebral creatine levels. Treatment of GAMT deficiency requires supplementation of ornithine and dietary restriction of arginine or protein. CRTR deficiency is treated with oral creatine monohydrate and arginine and glycine supplementation. The developmental delay, intellectual disability, and behavior problems are managed with an individualized education and therapy program; epilepsy and movement disorder are treated by the appropriate specialist in a standard manner.

Surveillance: In those treated with creatine monohydrate, periodic determination of cerebral creatine level by in vivo ¹H-MRS and annual measurement of renal function to detect possible creatine-associated nephropathy is warranted. Developmental and neurologic assessments are recommended at each clinic visit.

Evaluation of relatives at risk: Early diagnosis of neonates at risk for a CDD by biochemical or molecular genetic testing allows for early diagnosis and treatment.

Genetic counseling: GAMT deficiency (caused by pathogenic variants in GAMT) and AGAT deficiency (caused by pathogenic variants in GATM) are inherited in an autosomal recessive manner. CRTR deficiency (caused by pathogenic variants in SLC6A8) is inherited in an X-linked manner.

1. Autosomal recessive inheritance. If both parents are known to be heterozygous for a GAMT or GATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GAMT or GATM pathogenic variants have been identified in an affected family member, molecular genetic carrier testing and prenatal and preimplantation genetic testing are possible.

2. X-linked inheritance. Mothers who are heterozygous for an SLC6A8 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy; sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be heterozygotes and may develop clinical findings related to the disorder. Once the SLC6A8 pathogenic variant has been identified in an affected family member, molecular genetic testing to identify female heterozygotes and prenatal and preimplantation genetic testing are possible.