Chapter 28 – Disorders of Creatine Metabolism: Creatine Deficiency Syndromes and Movement Disorders

Abstract

Chapter 28 Disorders of Creatine Metabolism: Creatine Deficiency Syndromes and Movement Disorders

Saadet Mercimek-Andrews

Introduction

Creatine is synthetized from two amino acids, arginine and glycine, in the kidney, liver, and pancreas. Two enzymes that are involved in the synthesis of creatine are L-arginine: glycine amidinotransferase (AGAT) (EC 2.1.4.1), highly expressed in the kidney, and guanidinoacetate N-methyltransferase (GAMT) (EC 2.1.1.2), which is highly expressed in the liver. S-adenosylmethionine (SAM) is the methyl donor in creatine synthesis (Figure 28.1). After synthesis, creatine is taken up by high energy requiring organs such as brain, muscle and retina using the sodium chloride-dependent creatine transporter (CRTR). About 50% of creatine is derived from high-protein-content food in the diet and about 50% is synthetized in the body. Creatine deficiency disorders are inborn errors of metabolism involving creatine synthesis and transport. These disorders include GAMT deficiency (OMIM 612736), AGAT deficiency (OMIM 612718), and CRTR deficiency (OMIM 300352). GAMT is encoded by GAMT (OMIM 601240), AGAT is encoded by GATM (OMIM 602360), and CRTR is encoded by SLC6A8 (OMIM 300036). GAMT and AGAT deficiencies are inherited in an autosomal-recessive manner and CRTR deficiency is X-linked. There are <120 patients with GAMT deficiency, <20 patients with AGAT deficiency and <200 patients with CRTR deficiency reported in the literature [1]. The estimated carrier frequency of GAMT deficiency is 0.123% in the general population [2], that of AGAT deficiency is 1 in 929 in the general population [3], and the estimated carrier frequency of CRTR deficiency in females is 1 in 4,060 [4].

Figure 28.1 Overview of creatine synthesis and transport. Abbreviations: ADP, adenosine diphosphate; AGAT, L-arginine:glycine amidinotransferase; ATP, adenosine triphosphate; CK, creatine kinase; CRTR, creatine transporter; GAMT, guanidinoacetate N-methyltransferase.

The clinical features include global developmental delay, cognitive dysfunction, and behavioral problems in all three creatine deficiency disorders, and seizures and movement disorders in GAMT and CRTR deficiencies. Females with CRTR deficiency can be asymptomatic carriers or can present with a phenotype similar to males. Cerebral creatine deficiency on brain ¹H-MRS is the biochemical hallmark of the three creatine deficiency disorders. Urine, plasma, and cerebrospinal fluid (CSF) guanidinoacetate and creatine measurements differentiate the three creatine deficiency disorders. The diagnosis is confirmed by molecular analysis of GAMT, GATM, or SLC6A8 [1].

All creatine deficiency disorders are treated with creatine supplementation. GAMT deficiency is treated with ornithine supplementation and a protein- or arginine-restricted diet in addition to creatine. CRTR deficiency is treated with arginine and glycine supplementation in addition to creatine [1].

In this chapter, a general overview for creatine deficiency disorders with emphasis on GAMT and CRTR deficiencies and movement disorders as well as treatment outcomes is provided. Clinical features, diagnostic investigations, and treatment of all three creatine deficiency disorders are summarized in Table 28.1.

Table 28.1 Clinical features, diagnostic investigations and treatment of GAMT, AGAT, and CRTR deficiencies.

Disorder	GAMT deficiency	CRTR deficiency	AGAT deficiency
Clinical features	Global developmental delay and intellectual disability (100% of patients) (severe to mild)	Global developmental delay and intellectual disability (100% of patients) (severe to mild)	Global developmental delay and intellectual disability (100% of patients) (severe to mild)
	Epilepsy (86% of patients)	Epilepsy (59% of patients)	Seizures (12.5% of patients)
	Movement disorder (37.5% of patients)	Movement disorder (40% of patients)	No movement disorder
	Behavioral problems	Behavioral problems (85% of patients)	No behavioral problems
	No muscle weakness or myopathy	No muscle weakness or myopathy	Muscle weakness or myopathy (53% of patients)
Diagnostic investigations	Elevated guanidinoacetate in urine, plasma, and CSF	Elevated creatine to creatinine ratio in urine in males	Low guanidinoacetate in either urine or plasma and CSF
	Creatine deficiency on ¹H-MRS in males and females	Creatine deficiency on ¹H-MRS in males	Creatine deficiency on ¹H-MRS in males and females
	Sequencing of GAMT	Sequencing of SLC6A8 (in males and females)	Sequencing of GATM
Treatment	Creatine (400–800 mg/kg per day)	Creatine (100–200 mg/kg per day)	Creatine (400–800 mg/kg per day)
	Ornithine (400–800 mg/kg per day)	Arginine (400 mg/kg per day)
	Protein- or arginine-restricted diet	Glycine (150 mg/kg per day)

Creatine Deficiency Disorders

GAMT Deficiency

GAMT deficiency was first described in 1994 [5]. In three large case series of 97 patients, movement disorders were reported in 36% of those with GAMT deficiency [6–9]. The first of these studies (2006) reported movement disorders in 52% of the patients (14 of 27) with GAMT deficiency [6]. Half of those patients had complex neurological syndromes including extrapyramidal and pyramidal movement disorders. In 43% of those patients (6 of 14), an abnormal signal intensity in the bilateral globus pallidus was present on brain MRI. Treatment improved the movement disorder in 64% of the patients on either creatine supplementation or on the combined creatine and ornithine supplementation and protein- or arginine-restricted diet treatments.

A second study reported movement disorders in 27% of the patients (13 of 48) with GAMT deficiency [7]. The authors defined the movement disorder as dystonia, chorea, hemiballism, ataxia, and spasticity. The frequency of each movement disorder or the most common type was not reported in that study. Interestingly, one patient had paroxysmal episodes of ataxia associated with an acute illness; the episodes lasted for several days, followed by a slow but full recovery. The movement disorder was ameliorated in 54% (7 of 13) of the patients on treatment. In some of those patients, creatine supplementation was the only treatment, whereas the majority of the patients were treated with combined creatine and ornithine supplementation and a protein- or arginine-restricted diet.

A more recent study reported movement disorders in 37% of the patients (8 of 22) [9]. The youngest age of onset of a movement disorder was 3 months. The most common movement disorders were dystonia and ataxia. Three patients had one type of movement disorder, either ataxia or choreoathetosis, whereas five patients had more than one type of movement disorder in combination, such as ataxia and tremor; choreoathetosis and dystonia; dystonia, chorea and ataxia; myoclonus and bradykinesia; or ballismus and dystonia. Brain MRI was normal in four patients with movement disorders, whereas two patients with movement disorders had bilateral globus pallidus changes on brain MRI. Additionally, one patient with bilateral globus pallidus changes had no movement disorder. The movement disorder resolved in four patients (all on the combined creatine, ornithine, and a protein- or arginine-restricted diet plus or minus sodium benzoate). Three patients had no improvement in their movement disorder (two patients on the combined creatine, ornithine, and protein- or arginine-restricted diet and one patient on creatine monotherapy).

A late-onset movement disorder was reported in a teenager who presented with global developmental delay and seizures within the second year of life. At the age of 17 years, generalized dystonia affecting the face, neck, and limbs, bradykinesia, and ballistic movements were reported. Brain MRI showed bilateral increased signal intensities in the globus pallidus. In contrast, a 13-year-old younger sibling with GAMT deficiency did not have any movement disorder at the time of diagnosis [10].

In a cohort of eight patients, ataxia was reported in 50% of cases. All patients with ataxia were older than 6 years of age at the time of diagnosis of GAMT deficiency [11]. In a patient with early-onset global developmental delay, seizures and choreoathetosis developed in the second year of life [12]. Bilateral increased signal intensities in the globus pallidus in brain MRI caused suspicion of mitochondrial encephalopathy, leading to a muscle biopsy which showed deficient complex I activity. However, persistently low plasma and urine creatinine levels led to the diagnosis of GAMT deficiency at the age of 21 months [12].

Globus pallidus changes in brain MRI may or may not be associated with the movement disorder or its severity in patients with GAMT deficiency.

AGAT Deficiency

AGAT deficiency was first described in 2001 [13]. Sixteen patients from eight families have been reported as of 2015 [14]. Only one patient, diagnosed asymptomatically due to a positive family history, had normal neurocognitive function. The remaining 15 patients had various degrees of developmental delay or intellectual disability. About 50% of the patients had either muscle weakness or myopathy. None of them had any type of movement disorder reported to date.

CRTR Deficiency

CRTR deficiency was first described in 2001 [15]. In an international study of 101 males with CRTR deficiency, motor dysfunction such as a wide-based gait, dysarthria, ataxia, and clumsiness was reported in 29% of the males [16, 17]. Dystonia or athetosis including abnormal athetoid hand movements, intermittent dystonic posturing of the hands or wrists during walking, choreoathetoid movements, or dystonia of the face and upper limbs was reported in 11% of the males with CRTR deficiency [16]. A male diagnosed with dystonia at the age of 3 months who was investigated for mitochondrial disorders was diagnosed with CRTR deficiency following an absent creatine peak on brain ¹H-MRS and an elevated urine creatine to creatinine ratio [18].

Diagnosis of Creatine Deficiency Disorders

Creatine deficiency on brain ¹H-MRS is the biochemical hallmark of GAMT and AGAT deficiencies in males and females and of CRTR deficiency in males. Creatine on ¹H-MRS can be partially deficient or normal in females with CRTR deficiency. Urine, plasma, and CSF guanidinoacetate levels are elevated in GAMT deficiency, low (below the reference range or at the lowest level of the reference range) in AGAT deficiency, and normal in CRTR deficiency. The urine creatine to creatinine ratio is elevated in males with CRTR deficiency, whereas females can have mildly elevated or normal urine creatine to creatinine ratio [1]. The diagnosis is confirmed by direct sequencing of GAMT, GATM, or SLC6A8. Many next-generation sequencing panels for epilepsy and intellectual disability cover the creatine deficiency disorders, as does whole-exome sequencing. Homozygous or compound heterozygous variants in GAMT and GATM and a hemizygous or heterozygous variant in SLC6A8 confirm the genetic diagnosis. It should be noted that biochemical confirmation using brain ¹H-MRS and urine guanidinoacetate and creatine to creatinine ratio are essential to confirm the pathogenicity of variants [1]. GAMT and AGAT enzyme activity or creatine uptake can be measured in cultured skin fibroblasts and can further support a diagnosis. Two variants in GAMT are commonly reported in the literature: c.327G>A, a panethnic variant, and c.59G>C, a Mediterranean variant (Portugal, Spain, and Turkey) [1] .