Creatine transporter deficiency, an underdiagnosed cause of male intellectual disability

Abstract

X-linked creatine transporter deficiency is caused by the deficiency of the creatine transporter encoded by the SLC6A8 gene on Xq28. We here report a 3-year-old boy with global developmental delay, autism and epilepsy. He had a normal MRI of the brain. Brain magnetic resonance spectroscopy (MRS) subsequently showed an abnormally small creatine peak. His high urine creatine/creatinine ratio further suggested the diagnosis, later confirmed by hemizygous mutation detected in the SLC6A8 gene. His mother was also heterozygous for the same mutation. Supplementation with creatine monohydrate, arginine, and glycine (precursors of creatine) and supportive therapies, resulted in modest clinical improvement after 12 months. This case highlights the importance of doing MRS for boys with global delay/intellectual disability, autism and epilepsy even with a normal MRI of the brain, to pick up a potentially treatable cause.

Background

Non-syndromic intellectual disability (ID)/global developmental delay (GDD) is always a diagnostic challenge. In spite of exhaustive investigations, only a minority of patients can get a confirmed diagnosis.¹ Creatine transporter deficiency (CTD) underlies approximately 2% of X-linked ID.² This condition though remains underdiagnosed as routine investigations for ID, including MRI of the brain, are usually normal.

In this report, we describe a 3-year-old boy with genetically proven CTD who had presented with GDD, autism and epilepsy. This case emphasises the importance of careful clinical profiling, especially the association of ID/GDD with autism and epilepsy and the role of simple investigations like urine creatine/creatinine (Cr/Crn) ratio and magnetic resonance spectroscopy (MRS) of the brain to diagnose this condition.

Case presentation

Our index patient was born out of a non-consanguineous relationship with an uneventful perinatal history. He was a fussy eater in the first year of life with frequent episodes of gastrointestinal illnesses and a failure to thrive.

We saw him at the 3-year age due to concern about delayed development. At the time, he had still not started to walk unaided (video file) or speak. He had poor eye contact and limited interaction with peers. His parents were also concerned about his behaviour, especially frequent temper tantrums. There were no concerns about his hearing and vision. Before visiting us, he had four episodes of generalised convulsive seizures from 8 months of age. These seizures were easily controlled on sodium valproate. He was the only child of his parents (figure 1). His mother also had mild ID. Other members in the maternal side of the family were normal.

Figure 1.

Pedigree chart of the index patient

On examination, he was thin built with his weight and height below the third centile for his age. His head circumference was at the 50th centile for his age. He was an active child but would easily get upset and exhibited poor social interaction (video file). He had downslanting palpebral fissures with a prominent forehead but no other significant dysmorphism. On initial visit, a neurological examination revealed a normal facial expression and cranial nerve assessment. He had a supported broad-based hesitant gait (video file). He seemed to have hypotonia, with difficulty standing from a seated position, though could lift his arms well. He could not cooperate for a formal power assessment. All his reflexes were well preserved.

Investigations

Because of autism and ID and family history of ID, a possibility of metabolic disorders, especially phenylketonuria (PKU) and organic aciduria was considered. As he was thin built with proximal muscle weakness, a differential diagnosis of the myopathic process was also entertained. His MRI of brain, tandem mass spectroscopy for aminoacidopathies, including PKU, and urine gas chromatography mass spectroscopy for organic aciduria were unremarkable. His thyroid function test and serum creatinine phosphokinase performed to investigate for a muscle disorder with global delay, was also normal. His electroencephalogram had shown occasional generalised epileptiform discharges. As part of the standard evaluation of GDD with subtle dysmorphism, autism and behaviour issues, we also performed karyotyping, complete blood count and renal function test. All the results were normal, including serum creatinine of 53.05 µmol/L (normal range 44.21–88.42 µmol/L). Due to a history of GDD and autism in a male child with mild ID in mother, the possibility of CTD was considered.

MRS was performed in the child, which showed an abnormally low creatine peak (figure 2A). Urine Cr/Crn ratio checked showed an excess urinary excretion of creatine with a urine Cr/Crn ratio of 711.01 µmol/mmol (normal 0–434). The MRS of the mother was normal (figure 2B).

Figure 2.

(A) Magnetic resonance spectroscopy (MRS) of the index patient showing abnormally low creatine peak (white arrow), from a voxel taken at right centrum semiovale. (B) MRS of the child’s mother showing a normal creatine peak (white arrow), from a voxel taken at right centrum semiovale.

Next-generation sequencing for CTD showed a hemizygous point mutation (c.507G>A; P. (Trp169*) of SLC6A8 gene in the index case. The same point mutation in the heterozygous form was present in his mother, as well.

Treatment

He was started on high-dose oral creatine (400 mg/kg/day), arginine (150 mg/kg/day) and glycine (150 mg/kg/day) supplementation.³

Physiotherapy, occupation therapy and behaviour therapy for the motor delay and autism were also initiated. Arginine was discontinued after 3 months due to side effects.

Outcome and follow-up

After 12 months of treatment and supportive therapy, there was a modest motor and cognitive improvement perceived by family (video 1). His eye contact had improved and he had improved interaction with parents. His difficult behaviour was also easier to manage. He could now walk independently but still had balance issues (video file). He had also started to speak, with a vocabulary of 2–3 single words. His MRS of brain though did not show any change in the creatine peak. He could also not cooperate for a formal IQ assessment. As mother was a carrier of the mutation, genetic counselling was offered to family in view of significant recurrence risk in future pregnancies.

Video 1.

Download video file ^{(3MB, mp4)}

DOI: 10.1136/bcr-2020-237542.video01

Discussion

Creatine plays an important role in the regeneration of ATP at sites of high energy use (brain, muscle and heart).⁴ In humans, creatine is synthesised in the kidney and liver and a small amount is also obtained from our diet.⁵ The creatine transporter (CRTR) protein is responsible for the uptake of creatine into cells against a large concentration gradient.⁶ It is expressed in most human tissues, with maximum concentration in skeletal muscle and kidney.⁷

Creatine deficiency syndromes constitute a group of neurometabolic disorders which include two autosomal recessive conditions with impaired creatine synthesis (arginine glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency), as well as one X-linked defect of CTD due to defect in CRTR protein.⁸

A defect in the CRTR results in excess excretion of creatine in the urine. This subsequently results in brain creatine deficiency. This CRTR protein is encoded by the SLC6A8 gene which maps to the X chromosome (Xp28).⁷

The hallmark features of CTD are ID/GDD, severe speech delay and autistic behaviour in a male child.⁹ Up to 50% of patients also have easily controlled generalised epilepsy.⁹ Our patient was thin built, had short stature and had significant gastrointestinal issues in the first years—common observations in this disorder and one that should be sought in the history.⁹ Our patient also had significant motor delay, hence a possibility of an underlying myopathic process was also considered. Clinical presentations with significant motor dysfunction along with ID is not unusual in CTD.¹⁰

Learning difficulties or mild ID has been mentioned in several heterozygous females in the reported creatine transporter defect families.¹¹ A family history of ID on the maternal side of the family like in our case, can thus be a clue to this diagnosis.

However, the diagnosis is often missed, as the MRI is usually normal in this condition.⁹ Urine Cr/Crn ratio is a simple non-invasive test that can help to confirm this diagnosis.⁶ CTD is characterised by elevated Cr/Crn in the urine, due to reduced renal absorption of creatine in combination with reduced creatinine excretion. This can be further confirmed on MRS which shows an abnormally low creatine peak.⁸ The diagnosis is confirmed by molecular analysis of SLC6A8 gene.⁹

Most of the SLC6A8 variants have been reported in western population, and rarely in Asian patients.^{8 12}

Often heterozygous females have a normal urine Cr/Crn ratio and normal creatine peak on MRS.¹¹ DNA analysis of the SLC6A8 gene is the only reliable option for screening for a creatine transporter defect in females presenting with (mild) retardation ID.¹¹

Treatment of CTD is based on the hypothesis that correction of cerebral creatine depletion will improve the clinical outcome. Oral supplementation of a high dose of creatine and creatine precursors (arginine and glycine) are given with the aim to maximise creatine transport into the brain.¹³ Unfortunately, the poor uptake by creatine transporters in astrocytes often make these therapies ineffective.¹⁴

There have been variable clinical responses to these supplementations.^{13 15} In a recent systematic review of patients treated with the above strategy, one-third of patients had shown clinical response to treatment.¹³ This though was not often corroborated by an improvement in creatine peak on MRS,¹³ as we had also observed in our patient. Another recent study on treatment of CTD had shown that combined creatine, arginine and glycine therapy might not improve but stop disease progression in affected males.¹⁵

To conclude, CTD is an X-linked disease, with a non-specific presentation of GDD, autism and epilepsy. The MRI of brain is usually normal in this condition. Hence, all men with global delay/ID should have MRS included as part of their routine neuroimaging protocol. Limited resources for general anaesthesia may prevent early neuroimaging in many centres. In these cases, urine Cr/Crn is a simple non-invasive test to suggest this diagnosis.

Patient’s perspective.

My son had always been thin built with a lot of tummy issues in the first year and seizures. He was also late in learning to speak and walk. We were really frustrated as in spite of all these problems, his blood tests and brain scan were normal. We came to know of the diagnosis at 3 years of age after he had a special type of MRI called ‘MRS’ which showed that creatine was leaking from the body, leading to low creatine in the brain. We started to give him creatine and glycine with seizure medication and occupation therapy. Since then, he has shown some improvement with much better eye contact and less temper tantrums. He has also now started to speak a few words and is walking well. We are also happy that now he is able to attend special school. There has been lot of difficulties over the years in supporting him, especially with his behaviour. We are still hopeful that with his treatment and support at home and school, we will be able to optimise his abilities with aim that he could live independently.

Learning points.

• Creatine transporter deficiency is an X-linked disorder that presents with intellectual disability (ID), autism with behavioural issues, and often epilepsy.

• This condition remains underdiagnosed as metabolic testing and structural neuroimaging are usually normal.

• A urine creatine/creatinine ratio and/or magnetic resonance spectroscopy of the brain for creatine peak should be routinely requested in all male patients with ID and autism to identify this disorder.

• The diagnosis can be confirmed by molecular testing for SLC6A8 gene on the X chromosome.