INFANTILE ALEXANDER DISEASE WITH LATE ONSET
INFANTILE SPASMS AND HYPSARRHYTHMIA
Paprocka J1,*, Rzepka-Migut B2, Rzepka N2, Jezela-Stanek A3, Morava E4
*Corresponding Author: Dr. Justyna Paprocka, Department of Paediatric Neurology, School of Medicine
in Katowice, Medical University of Silesia, Medyków 16, 40-752 Katowice, Poland. Tel: +48-606-
415-888. Fax: +48-322-071-615. E-mail: justyna.paprocka@interia.pl
page: 77
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INTRODUCTION
Alexander disease (AxD) is a rare autosomal dominant
leukodystrophy with three clinical subtypes: infantile,
juvenile and adult. The neonatal forms were also described
[1-5]. Forms differ by age of symptoms occurrence and the
clinical picture. Although recent data suggest considering
only two subtypes: type I (infantile onset with lesions extending
to the cerebral hemispheres); type II (adult onset
with primary involvement of subtentorial structures). The
infantile subgroup with early onset within 2 years of life is
the most common. Dominant mutations in the glial fibrillary
acidic protein (GFAP) gene in AxD cause dysfunction
of astrocytes (a type III intermediate filament).
The disease manifests with macrocephaly, retarded
psychomotor development and seizures. Other common
symptoms are: ataxia [1,3,4,5], pyramidal signs [3,4,5],
including spasticity [1,4]. Magnetic resonance imaging
(MRI) shows demyelinating changes mainly in the frontal
lobes. Genetic background is a mutation in the GFAP gene
with variable clinical features. The authors present a case
of infantile onset AxD with normal head circumference.
Case Presentation. The authors present a boy with
an unremarkable family history, a second child of non
consanguineous parents, born vaginally at 41 weeks’ gestation.
The perinatal period was uneventful. He weighed
4280 g (50-90 percentile), his head circumference was
33.5 cm (3-10 percentile) and his birth length was 58 cm
(>97 percentile). The boy was rated 8 points in the Apgar
scale. The parents were concerned about the child’s delayed
development: independent sitting at 9 month, first
words at approximately 13 months, abnormal behavior, the
boy rarely cried and had no interest in toys. Because of
generalized hypotonia, the patient was rehabilitated since
his 8th month of life. Ultrasound examination of the head
performed at 12 months showed enlargement of the lateral
and third ventricle. Brain MRI (at the age of 13 months)
confirmed internal hydrocephalus and directed suspicion
to an aqueductal stenosis. Furthermore, it additionally
revealed spots of impaired myelination. Areas of diffuse hyperintensity of white matter in the frontal lobe, within
the left lentiform nucleus and in left-sided posterior part
of the internal capsule (Figures 1, 2 and 3). Features of
intracranial hypertension that might require neurosurgery
intervention were not found. At 18 months, the boy was
hospitalized due to a prolonged episode of left-sided seizures,
with secondary generalization followed by a longer
period of altered consciousness. At hospital admission, the
head circumference was 49 cm (75-90 percentile). On neurological
examination, meningeal symptoms were absent,
hypotonia (L>R) with preserved tendon reflexes, were
observed. Computed tomography of the brain excluded
intracranial hypertension, the size of the lateral ventricles
was comparable with previous MRI result (Figures 4 and
5). During the few next days of hospitalization, clusters of
epileptic spasms occurred. Frequent myoclonia were also
observed concomitant with temperature up to 38.4 °C. The
longest status epilepticus persisted for 8 hours. Because of
exposure to Herpes virus, serum and cerebrospinal fluid
examinations were performed, and Herpes infection was
excluded. Electroencephalography revealed generalized
paroxysmal activity, especially in temporal and occipital
areas in the form of a symmetric hypsarrhythmia. Inadequate
response to anticonvulsant treatment required many
drug modifications and was coupled with developmental
regression. Antiepileptic treatment (valproic acid and lamotrigine)
managed to stop seizures for 10 months.
The boy started sitting independently again, and
at approximately 2 years of age, he started walking and
speaking simple sentences, but the speech was unclear.
Later, he was repeatedly hospitalized due to intensification
of polymorphic seizures during infections. Neurological
examination showed the head circumference within the
range of 50-75 percentiles, hypotonia with preserved tendon
reflexes, wide-based gait and ataxia. Ophthalmologic
examination was normal. Based on performed metabolic
work-up, organic acidurias, lysosomal storage disorders,
peroxisomal disorders were excluded. Serum amino acids,
acylcarnitine profile, ammonia and lactate level and thyroid
function tests were within normal limits. Renal and
liver function tests, hearing evaluation, ultrasonography of
abdominal cavity did not show any abnormalities. Because
of the presence of fever-induced seizures, mutations in the
SCN1A gene were excluded.
The neuroimaging findings were suggestive of AxD
but macrocephaly did not occur during any period of his
life. The head circumference has never exceeded 2 standard
deviations. At the age of 5, molecular tests confirmed
presence of a de novo heterozygous mutation (c.236G>A)
in the GFAP gene, which is responsible for AxD. In the
parents’ samples, the described mutation was not detected.
At the present time, the boy is 7 years and 8 months old
and he is proceeding with an intensive rehabilitation. The
neurological picture slowly deteriorates, the child presents independent and unsteady gait, he cannot run or jump.
Vocabulary is limited to simple words and speech is still
unclear. He recognizes people, is friendly and open. There
have been no episodes of epileptic seizures since he was
3 years old; it may be partially connected with the less
number of infections, which acted as a trigger factor. Brain
MRI has been repeated once a year or once in 2 years, and
it is stable compared to previous examinations. The supratentorial
ventricular system is dilated, not displaced and
symmetrical. Hyperintensive signals are visible from white
matter in the frontal lobe with fragmentary insulas and
frontal parts of the external capsule in both hemispheres.
Additionally, MRI showed atrophy of white matter of the
occipital and parietal lobes. Focal points of incorrect signal
also include head of caudate nucleus and frontal part of
the left lentiform nucleus (Figure 2).
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