Galactosemia and phantom absence seizures.

Generalized and focal seizures can rarely be seen in galactosemia patients, but absence seizures were not reported previously. An 18-year-old male was diagnosed as galactosemia at the age of 8 months. No family history of epilepsy was present. His absence seizures realized at the age of 9 years. Generalized 3-4 Hz spike-wave discharges were identified in his electroencephalography. Homozygous mutation at exon 6 c. 563A > G was identified. The electroencephalogram of his sibling was unremarkable. Our aim was to present the long-term follow-up of a patient diagnosed with galactosemia, who had phantom absence seizures and typical 3-4 Hz spike-wave discharges in his electroencephalogram to draw attention to this rare association.

Introduction

Galactosemia is a metabolic disorder with an autosomal recessive inheritance, due to the deficiency of galactose-1-phosphate uridyl transferase (GALT). Galactose-1-phosphate amounts increase in the blood and accumulate in tissues, such as the central nervous system, eyes, liver, kidneys, and erythrocytes. The clinical picture appears with the toxic effect of its conversion to galactitol and oxidized galactone.[12] The incidence of galactosemia is variable in different populations.[3] In classic galactosemia, lethargy, difficulty in feeding, jaundice, hepatomegaly, and hypo tonicity are seen in the 1st day of the newborn after birth when it begins to consume milk. In the following weeks, newborn death may be observed due to newborn sepsis. In addition, mental retardation, growth and developmental retardation, cataracts, hormonal disorders, increased intracranial pressure, speech disorders, cerebellar and extrapyramidal findings, and rarely seizures[4] may be observed.[2] A galactose-free diet started as early as possible, may prevent the development of the clinical picture in the newborn period. However, chronic and progressive neurological disorders are possible in such patients in spite of dietary restrictions.[2] Generalized and sometimes focal seizures may ensue in patients with galactosemia as is generally expected in metabolic diseases.[4] However, absence seizures were not reported in the relevant literature. This study reports a case with galactosemia having phantom absence seizures in the video electroencephalogram, that were not noticed by the patient or his family before the identification of related typical 3 Hz spike wave discharges in the electroencephalogram.

Case Report

An 18-year-old male patient was born through a normal vaginal delivery at 40 weeks of gestational age; he did not cry at birth, and was recognized as hypotonic at birth, and after vomiting due to breast feeding, the patient began to be fed on formula. However, he continued to vomit in spite of the change to formula feeding. He was admitted to the hospital 1 week after birth with high bilirubin level and jaundice. The patient's condition improved in almost 1 week and was discharged with formula feeding. A short time after the discharge, he was admitted to the hospital again with complaints of abdominal swelling. A liver biopsy was performed and thereafter he was followed-up with the diagnosis of “cirrhosis.” He was admitted to the hospital frequently due to fever, pneumonia, and diarrhea and finally had a diagnosis of galactosemia with the identification of galactose-1-phosphate uridyl transferase deficiency in the serum and urine at the age of 8 months. Diet regulations were made. The first cranial magnetic resonance imaging of the patient was unremarkable at that time. The patient, whose motor development was delayed, held his head up at the age of 3 years, started sitting up, and later crawling and speaking at the age of 4 years. Sphincter control started at the age of 5 years.

He had a febrile convulsion when he was 3 months old. The mother and father were cousins, and three siblings of the patient were healthy. No history of epilepsy was present in the family. The family history revealed that a cousin of the patients’ mother had hydrocephalus, and a child of the patient's uncle had died during childhood with unknown cause. He was admitted to the hospital again at the age of 9 years due to agitation and staring during playing. The neurological examination of the right-handed patient revealed mental retardation (IQ: 36), convergent strabismus, bilateral Babinski, and hypoactivity of the deep tendon reflexes in the lower extremities. Upon physical examination, he was calm and shy and responded to the questions with single words. He had a chest deformity and external angulation in the knee joints. He was thin with a small stature and was hypotonic.

Interictal regular, generalized 3-4 Hz spike-wave discharges were identified in the routine electroencephalography examination [Figure 1a]. On these findings, a long-term video electroencephalogram was performed, and 3.5-4 Hz spikes and slow wave discharges lasting 4-5 s with high amplitude and anterior predominance were observed [Figure 1b]. The patient could not direct his attention during the discharges although he did not lose communication completely. He was started on 200 mg/day of valproic acid since he was thought to have phantom absence seizures. His family reported that his condition improved with the treatment. Afterwards, the patient had his first generalized tonic-clonic seizure at the age of 9.5 years, and the dosage of the drug treatment was increased according to the measured drug level.

Figure 1a

The electroencephalogram at the age of 9 years showed 3-4 Hz regular spike and wave discharges lasting 1-3 s

Figure 1b

Video electroencephalogram examination disclosed 3.5-4 Hz spikes and slow wave discharges lasting 4-5 s with high amplitude and anterior predominance. During these discharges, the patient could look to the examiner but could not answer appropriately

Hyperintense signal changes were identified in the subcortical white matter of the bilateral cerebral hemispheres in the cranial magnetic resonance imaging, when the patient was 13-year old [Figure 2]. On valproic acid treatment, the patient experienced one generalized tonic-clonic seizure yearly, during the 9 years of follow-up. The frequency of absence seizures (focusing at one point with no answer to calling and awakening with shaking off) decreased gradually and currently occurs at a rate of one every 2-3 months. His last treatment regimen consists of 1000 mg/day valproic acid and 1.5 mg/day risperidone for agitation. His last recorded height was 1.85 m and weight was 52 kg. Generalized spike-wave discharges continued at his last control electroencephalogram without any clear accompanying clinical findings.

Figure 2

Cranial magnetic resonance imaging demonstrated subcortical hyperintense signal changes throughout the cerebral hemispheres on both sides

Homozygous mutation at exon 6 c. 563A > G (rs75391579; p.Q188R, p. Gln108Arg) was identified in the analysis of the galactose-1-phosphate uridyl transferase gene. The electroencephalogram of his sibling was unremarkable.

Discussion

Classical galactosemia is a congenital disease of metabolism with autosomal recessive traits, which results from galactose-1-phosphate uridyl transferase enzyme deficiency at the metabolic pathway of galactose.[5] The galactose-1-phosphate uridyl transferase gene in humans resides in the p13 region of the ninth chromosome.[6] The most commonly seen mutation among the defined 167 mutations is the Q188R mutation.[1] We also identified this mutation in our Turkish patient, as well. The incidence of galactosemia varies throughout the world; the rate is 1:23,775 in Turkey,[7] whereas it is seen in 1:30-40,000 births in Europe,[8] 1:53,000 in the United States with newborn screening (National Newborn Screening and Genetics Resource Center; 2002 Newborn Screening and Genetic Testing Symposium). This increased frequency seen in our country is due to the increased rate of consanguineous marriages. The mother and father of our patient were children of cousins, which increases the frequency of a disease that has an autosomal recessive inheritance.

Clinically, neurological and nonneurological sequelae develop in cases with galactosemia due to the accumulation of galactose-1-phosphate in several tissues. Growth and developmental retardation might be seen; however, the last recorded height of our patient is normal. Our patient had a height within the normal range, although he was at a lower weight compared to his peers since he had a special diet. Cataracts are reported in about 30% of the patients and have a tendency to improve with galactose restriction in the early phases.[9] It is rarely severe enough to cause functional disorders. The lenses of our patients were removed at the age of 3 years due to bilateral cataracts.

The mean level of intelligence (IQ) was demonstrated to be low in many studies in galactosemic adults.[19] No associations between the cognitive functions of the patient and the time of diagnosis and time of treatment initiation were observed.[910] Disorders of motor function and speech may also be seen in patients with galactosemia, and severe progressive ataxia and tremor were also detected in about 10-20% of patients, despite early treatment.[49] Our patient did not have a progressive motor disorder and his compliance with daily activities were quite good when his low IQ level was taken into account.

Seizures were reported very rarely in patients with galactosemia.[2411] The types of the seizures reported in such cases are complex partial and generalized tonic-clonic seizures.[4] It was assumed that the frequency of seizures is low in galactosemia, and such epileptic patients might reflect the prevalence of epilepsy in the general population.[2] In the case presented here, mild absence seizures were also observed, which is different from the reported clinical pictures of the patients with galactosemia having seizures. The patient's electroencephalograms were also compatible with typical absence seizures. Although these seizures may be coincidental, they could be related to galactosemia since there was no family history of epilepsy and no generalized epileptiform discharges were identified in the 1-h electroencephalogram performed in the sibling of the patient. This is the first reported case of galactosemia with absence seizures. The staring seizures of the patient were not noticed by the patient and his family due to his mental retardation; the electroencephalogram findings guided the diagnosis. There were no associated symptoms such as eye blinking, and his consciousness was not severely disordered during his seizures; thus, his absence seizures were evaluated as “phantom” absence seizures. Phantom absences was described as consisting of mild ictal impairment of cognition associated with brief (3-4 s), generalized 3-4 Hz spike/multiple spike and slow wave discharges related to idiopathic generalized epilepsy syndromes in the relevant literature.[12]

The association of the identified GALT mutation with absence seizures is obscure at this point. Absence seizures are typically seen in idiopathic generalized epilepsy (IGE) syndromes such as childhood and juvenile absence epilepsy, and idiopathic generalized epilepsy syndromes are common, heritable epilepsies that, usually, follow complex inheritance. Currently, little is known about their full-blown genetic architecture. However, it was demonstrated that many IGEs are ion channelopathies while many other mutations encode for ubiquitary enzymes that play crucial roles in various metabolic pathways.[13] Furthermore, relationship between some neurometabolic disorders and absence seizures was already described, especially for glucose metabolism disorders. SLC2A1 mutations contribute to approximately 1% of idiopathic generalized epilepsy both as a dominant gene and as a susceptibility allele in complex inheritance. Therefore, there is increasing need for studies investigating the mechanisms underlying absence seizures in association with various metabolic defects.

Conclusion

Our case report showed a rare association of galactosemia with absence seizures. This could be either a coincidental association or reflect unknown mechanism underlying absence seizures. We would like to stress that the clinicians managing galactosemic patients should be alert to diagnose possible mild absence seizures and include electroencephalogram as an essential part of the follow-up.