A 6-year-old boy was born to first-degree healthy consanguineous Tunisian parents. His family history was unremarkable, in particular, no sibling or other relative affected in the family. Pregnancy and delivery were uneventful. His past medical history was significant for esotropia surgery at the age of 4. He had no history of epilepsy.
He presented with psychomotor delay (walk acquired at 2 years, language acquisition at 4 years), gait imbalance, and movement disorder. Symptoms worsened after physical exertion.
Examination showed normal head circumference (52 cm), mild mental retardation and language delay, cerebellar syndrome, and generalized chorea (see Video 1). There was no sign of oculomotor apraxia and no telangiectasia.
Diagnosis of autosomal recessive cerebellar ataxia was initially discussed, particularly ataxia telangiectasia and ataxia with oculomotor apraxia type 1 and 2. Brain MRI was normal. Myoclonic jerks were not noticed during electrophysiological studies. Routine blood tests, thyroid tests, blood cholesterol, albumine, immunoglobulin A, and alpha-fetoprotein were normal. Karyotype was normal and fragile X syndrome was excluded.
Diagnosis of GLUT1 deficiency syndrome was suggested on the basis of the worsening of symptoms after exercise; cerebrospinal fluid (CSF) analysis revealed hypoglycorrhachia at 1.7 mmol/L (normal, 2.7–4.0) with a CSF/blood glucose ratio at 0.35 (normal, <0.45). CSF lactate was normal. Genetic study of the SLC2A1 gene showed a heterozygous mutation c.966delC (p.Val323Cysfs*17), confirming the diagnosis of GLUT1 deficiency syndrome. This mutation was found in his asymptomatic mother. The father was tested and found to be negative, confirming the autosomal-dominant transmission.
A ketogenic diet was initiated in November 2013, and after a follow-up of 12 months, the movement disorders did not improve.
We report on the case of a Tunisian child with an atypical presentation of GLUT1 deficiency syndrome resulting from a novel dominant mutation. The classical presentation of GLUT1 deficiency is intractable epilepsy that starts in the first 6 months after birth, psychomotor delay, ataxia, complex movement disorders, and microcephaly.[1, 2]
This typical phenotype rapidly expanded. Atypical forms were described without seizures, with early-onset absence epilepsy, paroxysmal events, alternating hemiplegia as adults with GLUT1DS, or paroxysmal exertion-induced dystonia and predominant choreoathetosis, as in our patient.[1-4]
The diagnosis of GLUT1 is confirmed by CSF analysis after a 4- to 6-hour fast: CSF glucose concentration was <2.2 mmol/L and glucose CSF/plasma ratio was <0.45.[1, 2] Although hypoglycorrhachia represented the biochemical hallmark, the molecular analysis of theSLC2A1 gene (chromosome 1p35-P31.3) has become the alternative gold standard for the diagnosis of GLUT1 deficiency syndrome. Approximately 100 mutations have been described in the SLC2A1 gene.[1, 2] Mutations in this SLC2A1 gene result in functions loss with altered glucose transport into the brain. Said alterations lead to cerebral energy deficiency, which is likely deleterious for brain development and functions. Most GLUT1 deficiency syndrome patients have heterozygous de novo mutations resulting in sporadic cases. Familial forms with autosomal-dominant and less-frequent autosomal-recessive transmission have been reported. No clear genotype-phenotype correlation has been established. Patients with the same frequent mutation, Arg126His, exhibit a heterogeneous range of type and severity of symptoms. Furthermore, GLUT1DS presentation seems to evolve with age, epilepsy decreases with age, whereas paroxysmal exercise-induced dystonia becomes more frequent, and, finally, ataxic-spastic gait worsens with age. Familial cases present mild phenotype with benign epilepsy in infancy and/or slight movement disorder or borderline IQ.
Here, we report a novel heterozygous autosomal-dominant mutation, c.966delC (p.Val323Cysfs*17), in the SLC2A1 gene as a cause of progressive chorea, yet inherited from an asymptomatic mother. It is possible that penetrance was, in a few rare cases, incomplete, which can be explained by a modulating effect of DNA variant regulatory elements of the wild-type GLUT1 allele on expression level of GLUT1 transport. Alternatively, the mother could have a mild undetected phenotype.
Ketogenic diet represents the therapy of choice for treatment of GLUT1 deficiency syndrome. Ketones provide an alternative fuel source for brain metabolism that is likely very effective on seizure control and movement disorders.[1, 2] However, efficiency is challenging because of compliance problems. Our case was not fully compliant, which explains the absence of significant improvement. Another therapeutic alternative is acetazolamide, which has been found to be effective against movement disorders, in some cases.[10, 11]
GLUT1 deficiency syndrome is likely misdiagnosed as a result of clinical spectrum width. The diagnosis should be considered in patients with movement disorders, particularly when the movement disorders are exercise induced or worsened. Recognition of this syndrome is important for clinical practice given that it is potentially treatable.