Keywords
Newborn - galactosemia - lumbar puncture - herniation
Galactosemia is a rare autosomal-recessive metabolic disorder affecting 1 in 30,000
to 60,000 infants. Hereditary galactosemia is among the most common carbohydrate metabolism
disorders and can be life-threatening during the newborn period. During the initial
hospitalization for a child with symptomatic severe classic galactosemia, the major
concerns are sepsis, bleeding, liver dysfunction, and brain swelling.[1] Cerebral edema with resulting elevated intracranial pressure is a well-known complication
of galactosemia. We present the case of a 3-week-old infant with galactosemia who
presented with signs of cerebellar herniation after lumbar puncture (LP).
Case Report
A 22-day-old female infant was referred to the neonatal intensive care unit because
of feeding difficulties, lethargy, jaundice, and hepatomegaly. She was born at 40
weeks' gestation by uncomplicated vaginal delivery. Her weight was 3200 g. Prenatal
and natal history was unremarkable. The Apgar scores were 8 and 9 at 1 and 5 minutes,
respectively. On the second day of life, she was hospitalized because of jaundice
and given phototherapy for 10 days. After discharge, she stayed at home until day
22 of postnatal life and showed progressive lethargy, feeding intolerance, and prolonged
hyperbilirubinemia. Family history was unremarkable for metabolic disorders. There
was no consanguinity between the parents. Her two brothers died about 3 months of
age.
On initial evaluation, the patient was lethargic with a temperature of 36.8°C, pulse
of 158 beats per minute, respiratory rate of 52 breaths per minute, blood pressure
of 78/36 mm Hg, and oxygen saturation of 98% on room air. Physical examination revealed
bulging anterior fontanel, jaundice, hepatomegaly, and ascites. The pupils were equal
in size and reactive to light. The patient was hypoactive and hypotonic. She was not
dehydrated and appeared to be in a fairly satisfactory state of nutrition. The liver
was enlarged to 5 cm below the costal margin along the midclavicular line, and there
was moderate ascites. There were no petechial lesions or mucosal bleeds.
Laboratory studies showed hemoglobin 13.4 g/dL, leukocytes 28 × 109/L, and platelets 547 × 109/L. Serum C-reactive protein value was 3 mg/dL (normal 0 to 1). The patient had normal
red cell morphology with occasional polychromasia, reticulocyte count of 4.6% in blood
smear, and immature to total neutrophil ratio on admission (0.22).The biochemical
markers were as follows: glucose 85 mg/dL, serum aspartate aminotransferase 314 IU/L,
alanine aminotransferase 257 IU/L, alkaline phosphatase 314 IU/L, gamma-glutamyltransferase
14 IU/L, total bilirubin 11.5 mg/dL, conjugated bilirubin 10.6 mg/L, albumin 2.2 g/dL,
blood urea nitrogen 31 mg/dL, and creatinine 1.48 mg/dL. Prothrombin time and activated
partial thromboplastin time were 23 (10.0 to 15.0) and 79 seconds (26 to 55 seconds),
respectively. Plasma ammonium was 339 μmol/L (reference range: 64 to 107 μmol/L),
and plasma lactate level was only mildly elevated (3.7 mmol/L). Arterial blood gases
(room air) showed pH of 7.25, base deficit of −7.2, PCO2 45 mm Hg, HCO3 17 mmol/L, PO2 74 mm Hg, and O2 saturation 91%. LP was performed for the diagnosis of clinically suspected bacterial
meningitis. Cerebrospinal fluid (CSF) analysis showed a white blood cell count of
60/mm3 with 70% polymorphonuclear cells and 30% lymphocytes, glucose 55 mg/dL, and protein
93.3 mg/dL, with negative Gram stain. Blood, urine, and CSF culture were negative.
Fifteen minutes after the LP, she became hypotensive with shallow respirations and
exhibited posture change. She was promptly intubated and stabilized with mechanical
ventilation. The pupils were fixed and dilated with absent corneal and gag reflexes.
The clinical suspicion of galactosemia was strengthened by finding positive reducing
substances in the urine. All other investigations including TORCH (To
xoplasma gondii, rubella, cytomegalovirus, and herpes simplex virus) serology and amino acids in the blood and urine level were normal.
Abdominal ultrasonography revealed an enlarged liver with ascites.
Diffusion-weighted magnetic resonance images revealed edema and diffuse cortical diffusion
restriction ([Fig. 1]). T1- and T2-weighted images revealed intensity increase in the deep white matter
of both cerebral hemispheres and edema of the entire cerebral hemisphere and basal
ganglia structures. The cerebellar tonsils were “herniated” through the foramen magnum
into the upper cervical spinal canal ([Fig. 2]).
Figure 1 Diffusion-weighted magnetic resonance image (A) and apparent diffusion coefficient
map (B) show extensive ischemia in the brain stem and supratentorial brain with relative
sparing of the white matter.
Figure 2 T2 sagittal section revealed cerebellar tonsillar herniation and compression of spinal
cord.
The enzyme activity of galactose + phosphate uridyl transferase (GALT) was further
determined quantitatively in erythrocyte lysate (by H.K.J.) by an isotopic method
using carbon-14 galactose-1-phosphate and uridine diphosphate galactose–glucose. GALT
activity in the patient was 0.55 U/g hemoglobin (>3). Three common mutations of GALT
gene in classical galactosemia, Q188R, S135L, and N314D, were screened by polymerase
chain reaction amplification of genomic DNA and restriction digestion. Homozygous
Q188R mutation was observed.
Discussion
Galactosemia is a disorder caused by a deficiency of any of the three possible enzymes
involved in the metabolism of galactose: galactokinase, transferase, or epimerase.
The natural history of classical galactosemia is lethargy, poor feeding, jaundice,
and hepatomegaly. These findings appear within days of the initiation of milk feedings.
Progression of this acute neonatal toxicity syndrome may include the development of
Escherichia coli septicemia in the second week of life, coagulopathy, hyperchloremic metabolic acidosis
with aminoaciduria, and vitreous hemorrhage.[2]
Neurologically, these patients may develop encephalopathy and signs of increased intracranial
pressure with cerebral edema, usually after several days of more nonspecific signs.
Galactosemia must be considered in the differential diagnosis of an infant with diffuse
cerebral edema presenting with a bulging anterior fontanel in the setting of poor
feeding, jaundice, and hepatomegaly.[3]
Animal models have suggested that the cerebral edema may be caused by elevations in
brain galactitol concentrations and alterations in glucose, adenosine triphosphate,
and phosphocreatine levels, which increase osmolality. The mechanism may be similar
to that reported in a rat model with intact GALT but excessive dietary loading, in
which galactitol accumulates in peripheral nerves and produces edema with increased
pressure and eventual demyelination.[4]
Liver failure is a rare presenting feature in the neonatal period, and potential etiologies
include inborn errors of metabolism, infections, ischemia, and abnormal perfusion.
Common metabolic causes include galactosemia, fructosemia, tyrosinemia type 1, and
bile acid synthesis defects.[5] Our infant had severe acute liver failure on presentation as evidenced by severe
coagulopathy and elevated liver enzyme (international normalized ratio of 2.4). The
hyperammonemia probably resulted from liver immaturity and the hepatotoxic effect
of elevated galactose metabolites,
Early recognition of meningitis is of prime concern in neonates because of the increased
morbidity and mortality associated with delayed or missed diagnosis. LP and a CSF
examination should be performed if meningitis is suspected or if increased intracranial
pressure from hydrocephalus is causing apnea and bradycardia. The most common purpose
for an LP is to collect CSF in a case of suspected meningitis, because there is no
other reliable tool with which meningitis, a life-threatening but highly treatable
condition, can be excluded.[6] LP was performed for the diagnosis of clinically suspected bacterial meningitis.
Fifteen minutes after the LP, she became hypotensive with shallow respirations and
exhibited decerebrate posturing. She was promptly intubated and stabilized with mechanical
ventilation.
Herniation of cerebral tissue through the foramen magnum is not a common problem in
neonatal intensive care units because of the open fontanelle in infants.[7] Herniation in neonates is very rare, traditionally attributed to the increased compliance
of the neonatal skull. In the literature, we found only two such case involving a
5-day-old infant with bacterial meningitis and a 1-day-old infant with uncal herniation
due to a large cerebral infarct.[8]
[9] Possible explanations for why cerebellar herniation occurred in our patient in the
absence of increased head circumference include the skull not being normally compliant,
swelling and subsequent increase in intracranial pressure occurring too fast to accommodate
increased volume with a normally compliant skull, or dura constraining the infarct
as swelling occurred, despite a compliant skull.
Infants with galactosemia may present with signs of increased intracranial pressure,
and central nervous system imaging has demonstrated the presence of diffuse cerebral
edema in some cases. This will generally resolve with appropriate treatment. As in
our case, fatal cerebral herniation may occur after LP. Even with an open anterior
fontanelle in a newborn, LP must be done carefully.
