Mild Phenotype Associated with SLC6A1 Gene Mutation: A Case Report with Literature Review

Abstract

The Solute Carrier Family 6 Member 1 (SLC6A1) gene encodes the gamma-aminobutyric acid (GABA) transporter 1, which is one of the main GABA transporters. The clinical picture of SLC6A1 gene mutations is characterized by a broader spectrum including a mild-to-moderate intellectual disability, speech difficulties, behavioral problems, epilepsy (often with myoclonic-atonic and atypical absence seizures, characterizing a myoclonic-atonic epilepsy), and neurological signs. We describe a boy with an SLC6A1 mutation and a milder phenotype, characterized by a learning disorder without intellectual disability, nonspecific dysmorphisms, and an electroencephalogram picture closely resembling that of myoclonic-atonic epilepsy with brief absence seizures that have appeared during the follow-up, responsive to valproic acid.

Introduction

The gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the central nervous system and its alterations are involved in the pathogenesis of epilepsy.[1] The Solute Carrier Family 6 Member 1 (SLC6A1) gene encodes the GABA transporter 1 (GAT-1), which is one of the main GABA transporters. GAT-1 has a critical role for the GABA reuptake from the synapses.[2] The clinical picture of SLC6A1 gene mutations is characterized by a broader spectrum including a mild-to-moderate intellectual disability, speech difficulties, behavioral problems (such as hyperactivity, attention deficit, aggressiveness, and autistic traits), epilepsy (often with myoclonic-atonic and atypical absence seizures, characterizing a myoclonic-atonic epilepsy), and neurological signs (ataxia or unsteady gait, hypotonia, tremor, and fine-motor impairment).[3,4]

We describe a boy with an SLC6A1 mutation and a mild phenotype.

Case Report

Family history was negative for neurological and psychiatric disorders. Pregnancy was normal except for a threatened abortion in the second month. Neonatal period was normal. Psychomotor development was normal. At 2 years, he was operated on for unilateral cryptorchidism. He has always had a slight impairment in gross motor skills. Since the first year of primary school, he showed a learning disability in reading, writing and arithmetic. He was left-handed. At our first observation (8 years), neurological examination showed a mild gross motor impairment, but no focal signs. He appeared as a quiet child, able to communicate verbally in an appropriate way, and without problems of socialization. The boy presented with low weight, short stature, and some dysmorphisms such as high anterior hairline, arched eyebrows, anteverted nostrils, hypertelorism, low-set and small ears, pectus excavatum, winged scapulae, dorsal spine scoliosis, fetal pads, and flat feet. The electroencephalogram (EEG) showed frequent epileptiform discharges of diffuse bilateral ~3.5 Hz spikes/polyspikes and waves prevailing on the anterior regions, increased during sleep and during hyperpnea, apparently without clinical correlates. Background activity was normal. At first clobazam and then acetazolamide were ineffective on EEG abnormalities. Since the age of 12 years, the aforementioned EEG epileptiform discharges have been sometimes associated with eyelid myoclonias and an increase in response latency (brief absence seizures) [Figure 1]. Therefore, we started him on a treatment with valproic acid as monotherapy, and the EEG immediately showed a marked decrease in epileptic discharges. At 6 years, Wechsler Intelligence Scale for Children (WISC) Third Edition showed a full intelligence quotient (IQ) = 102, verbal IQ = 99, and performance IQ = 104. No cognitive deterioration has been detected during the follow-up: in fact, at 12 years full IQ was = 107 (WISC-IV). Brain magnetic resonance imaging was normal. Genetic counseling has led to the array comparative genomic hybridization, which was normal, to the molecular search for Fragile X syndrome (negative), and finally to a next-generation sequencing (NGS) multigene panel for neurodevelopmental disorders that showed a heterozygous missense variant in SLC6A1 gene, exon 16 (c.1697G>A; p.Arg566His). This gene variant was present also in the father, who was apparently healthy. Therefore we performed EEG in the father (at the age of 60 years), which was normal. EEG of the father during childhood and adolescence was not available.

Figure 1.

Electroencephalogram recording during wakefulness at the age of 12 years (see the text for details)

Discussion

Literature data suggest that the typical phenotype in individuals with SLC6A1 gene mutations includes intellectual disability, behavioral problems, epilepsy (often characterizing a myoclonic-atonic epilepsy), and neurological signs.[3,4] Our case report shows that SLC6A1 gene mutations could be associated also with a milder phenotype, characterized by a learning disorder without intellectual disability, nonspecific dysmorphisms, and a clinical and EEG picture closely resembling that of myoclonic-atonic epilepsy, with brief absence seizures that have appeared during the follow-up, responsive to valproic acid. The fact that the same genetic variant was found also in the father, at least apparently healthy, does not rule out its pathogenicity because the expressivity of SLC6A1 gene mutations is variable and little is known about the longitudinal follow-up of these cases.[4] In fact, we cannot exclude that as a child the father had an EEG picture similar to that of his son and possibly also his brief absence seizures, the existence of which was not perceived by the parents in everyday life.

According to Johannesen et al.,[4] the role of epilepsy in the development of the intellectual impairment in individuals with SLC6A1 mutations is questionable: in 16 of their 24 cases (about 67%) for which the data were available, there was an intellectual disability even before the onset of seizures. After epilepsy onset, intellectual functioning worsened in 11 out of 24 cases (about 46%), without improvements after achieving seizure control.[4] Our case had a very good response to valproic acid administered as monotherapy. This, in light of the mutation of the SLC6A1 gene, was predictable as the valproic acid enhances the action of GABA by inhibiting its degradation and increasing its production.[5] And in fact valproic acid has been yet used with good effects just in cases with SLC6A1 gene mutations.[4]

In conclusion, this case report suggests also some general considerations regarding the genetic diagnosis in child neurology. First of all, the use of an NGS multigene panel can be useful to discover atypical cases characterized by clinical features considered hitherto incomplete. Furthermore, the EEG findings at least in some cases can be a biological marker useful for orientating the genetic tests. Finally, genetic diagnosis can be useful not only for a genetic counseling but also for correctly addressing the antiepileptic therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.