Clinical Guidance

No clinically relevant genotype-phenotype correlations for any of the CDDs have been identified.

Source: GeneReviews — "Creatine Deficiency Disorders"

Diagnostic Criteria

The creatine deficiency disorders (CDDs) are inborn errors of creatine metabolism and transport that comprise:

• Two creatine biosynthesis defects (both inherited in an autosomal recessive manner):

• Guanidinoacetate methyltransferase (GAMT) deficiency

• L-arginine:glycine amidinotransferase (AGAT) deficiency

• One creatine transporter defect (inherited in an X-linked manner): creatine transporter (CRTR) deficiency

Suggestive Findings

A CDD should be suspected in probands with the following clinical, biochemical, and imaging findings and family history.

Clinical findings

Source: GeneReviews — "Creatine Deficiency Disorders"

Differential Diagnosis

Disorders summarized in should be considered in individuals with partial creatine deficiency in the brain detected by 1H-MRS, who have normal concentrations of guanidinoacetate (GAA) in the urine, plasma, and CSF and a normal creatine-to-creatinine ratio in urine.

Table 3.

Disorders of Interest in the Differential Diagnosis of Creatine Deficiency Disorders

Gene | Disorder | MOI | Biochemical Features | Clinical Features

ALDH18A1

| P5CS deficiency1 (See Neurocutaneous Disorders due to Mitochondrial Proline Synthesis Defects.) | ARAD | Secondary (cerebral) creatine deficiency | Dysmorphic features, DD, spasticity, myopathy, slow growth

Source: GeneReviews — "Creatine Deficiency Disorders"

Management Guidelines

No clinical practice guidelines for creatine deficiency disorders (CDDs) have been published. Some of the references list management recommendations for GAMT and CRTR deficiencies .

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a CDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Creatine Deficiency Disorders

System/Concern | Evaluation | Comment

Neurologic

| Neurologic eval | • Brain 1H-MRS to document creatine deficiency if not done as part of diagnosis

• EEG if any clinical seizures or suspicion of seizures

Development

| Developmental/neuropsychologic assessment | • Incl motor, adaptive, cognitive, speech-language eval

• Eval for early intervention/ special education

• Eval of cognitive functions w/objective tests to measure IQ

Movement

disorder1 | • Orthopedics/ physical medicine rehab/ PT/OT eval

• Video documentation of mvmt disorder

| Incl assessment of:

• Gross motor fine motor skills

• Mobility, ADL, need for adaptive devices

• Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)

Behavioral

| Neurobehavioral eval | For persons age 12 mos screening for:

• Behavior concerns

• Sleep disturbances

• ADHD

• Anxiety

• Findings suggestive of ASD

Potential for

treatment-assoc

nephropathy | Baseline kidney function studies | • Blood urea

Source: GeneReviews — "Creatine Deficiency Disorders"

Therapies Under Investigation

There are no current clinical trials for any of the CDDs. Some pharmacotherapies are being investigated in cell lines or animal models of CRTR deficiency:

Source: GeneReviews — "Creatine Deficiency Disorders"

Surveillance Guidelines

Surveillance recommendations for CDDs are summarized in .

Table 9.

Recommended Surveillance for Individuals with Creatine Deficiency Disorders

System/Concern | Evaluation | Frequency

Development

| Monitor developmental progress educational needs. | At each visit

Neurologic

| Monitor those w/seizures as clinically indicated.

Assess for new manifestations such as seizures, mvmt disorders, behavioral problems.

For those

undergoing

treatment of

low cerebral

creatine levels | Determination of cerebral creatine level by in vivo 1H-MRS | • For those w/GAMT or AGAT deficiency: to monitor cerebral creatine levels during creatine supplementation therapy

• For those w/CRTR deficiency: to monitor cerebral creatine levels for assessment of treatment outcome

Assess kidney function (GFR) while on creatine supplementation therapy to detect possible creatine-assoc nephropathy in GAMT, AGAT, CRTR deficiencies. | Annually

For GAMT deficiency, assess:

• Growth nutritional status;

• Plasma GAA levels, plasma amino acids, ammonia, protein, albumin, pre-albumin levels.

| Every 3-6 mos

For AGAT deficiency, no surveillance labs needed |

For CRTR deficiency, assess plasma GAA levels plasma amino acids.1 | Every 3-6 mos

GAA = guanidinoacetate; GFR = glomerular filtration rate

1. High-dose arginine and glycine supplementation can result in increased GAA levels.

Source: GeneReviews — "Creatine Deficiency Disorders"