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February 08, 2000; 54 (3) Brief Communications

Acute hydrocephalus in nonketotic hyperglycinemia

J.L. K. Van Hove, P.S. Kishnani, P. Demaerel, S.G. Kahler, C. Miller, J. Jaeken, S.L. Rutledge
First published February 8, 2000, DOI: https://doi.org/10.1212/WNL.54.3.754
J.L. K. Van Hove
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P.S. Kishnani
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P. Demaerel
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S.G. Kahler
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C. Miller
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J. Jaeken
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S.L. Rutledge
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Citation
Acute hydrocephalus in nonketotic hyperglycinemia
J.L. K. Van Hove, P.S. Kishnani, P. Demaerel, S.G. Kahler, C. Miller, J. Jaeken, S.L. Rutledge
Neurology Feb 2000, 54 (3) 754; DOI: 10.1212/WNL.54.3.754

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Abstract

Article abstract We present four patients with typical neonatal onset nonketotic hyperglycinemia (NKH) who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The three older patients had profound developmental disabilities. This suggests that the development of hydrocephalus in NKH is an additional poor prognostic sign.

In nonketotic hyperglycinemia (NKH), deficient glycine cleavage enzyme activity produces increased glycine levels in blood and CSF, with an increased CSF to plasma glycine ratio. Infants present in the first days of life with lethargy progressing to coma, pronounced hypotonia, myoclonic seizures, and apnea. The EEG shows a burst suppression pattern. Spontaneous breathing resumes after 1 to 2 weeks. Psychomotor development is delayed, and axial hypotonia, peripheral spasticity, few spontaneous movements, poor head control, and severe seizures are common. Variant late-onset forms and transient forms have been reported.

Even in patients presenting as a neonate, developmental outcome is variable; some have moderate mental retardation and achieve independent walking, while others do not make any developmental progress. Recent studies have suggested that factors other than glycine kinetics may be important for these differences in developmental outcome, including prenatal malformations.1,2 Reported malformations include a hypoplastic or absent corpus callosum, delayed to absent myelination,3 gyral malformations, and cerebellar hypoplasia.4 In this study, we describe four patients with neonatal onset NKH who developed acute hydrocephalus and a posterior fossa cyst.

Case reports.

Case 1.

In the first 3 days of life, this baby girl became hypotonic and lethargic, had clonic movements, and was intubated for apnea. Electroencephalogram showed a burst suppression pattern. The plasma glycine level was 830 μM, the CSF glycine level was 218 μM, with a CSF to plasma glycine ratio of 0.26. Urine organic acids were normal. A diagnosis of NKH was made, and she was treated with 500 mg/kg of sodium benzoate per day, 7.5 mg/kg of dextromethorphan per day, ranitidine, phenobarbital, and d-serine. A CT scan on day three of life showed mild dilatation of the lateral ventricles posteriorly greater than anteriorly, as would be seen in partial absence of the corpus callosum (figure, A). The ventricular dilatation was slightly increased at the end of the first week. There was no evidence of brain atrophy. Infantile spasms appeared at age 31/2 months and were treated with vigabatrin. At age 41/2 months, an acute increase in head circumference to above the 95th percentile was associated with vomiting, a bulging fontanel, and increased flexor spasms. Computed tomography scan showed pronounced enlargement of all ventricles with effacement of sulci, and decreased attenuation around the frontal horns suggestive of transependymal egress of fluid (figure, B). Dilatation of the optochiasmatic cistern suggested that hydrocephalus had been present for some time before the scan. A ventriculoperitoneal shunt was placed, and MRI showed a decreased ventricular size (figure, C). On sagittal images (figure, D), the corpus callosum was markedly thinned. There was a posterior fossa cyst that caused anterior and superior displacement of the cerebellar vermis. This was not noticeable on the images in the first week of life. There was no evidence of gyral malformations. Myelination was absent in the internal capsule and in the dorsal brainstem. Follow-up MRI 10 months later showed persistent ventriculomegaly. At age 1 year and 5 months, the patient had severe axial hypotonia, hyperreflexia, and dystonic posturing. She had no grasp reflex. She reacted to sound and touch, but not to visual stimuli. Gastrostomy tube feeding was required. Her head circumference had decreased to the 95th percentile. Medications included sodium benzoate, dextromethorphan, and vigabatrin.

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Figure. CT scan of Patient 1 taken in the first week of life (A), CT scan taken at age 41/2 months at the time of the hydrocephalus (B), and MRI imaging after shunting at age 5 months in the axial (C) and sagittal plane (D).

Case 2.

Details of this patient’s history have been previously reported.5 On the second day of life, he became hypotonic with poor sucking and with clonic jerks. He was ventilated for apnea from days 5 to 22 of life. His plasma glycine was 795 μM, and CSF glycine was 167 μM, rendering a CSF to plasma glycine ratio of 0.21. Urine organic acids were normal. The CT scan at 8 days of life showed normal sized ventricles, absence of the corpus callosum, and a small to moderate posterior fossa cyst. At diagnosis on day 36, he was hypotonic, hyperreflexic, and had frequent myoclonic seizures. After treatment with clonazepam, 3 mg/kg of dextromethorphan per day, and sodium benzoate with doses up to 750 mg/kg per day that resulted in plasma glycine levels dropping to less than 200 μM, there was improved seizure control and increased alertness. At age 4 months, he showed increased irritability, lethargy, poor sucking, and a bulging anterior fontanel. The head circumference had increased to well above the 95th percentile. Plasma glycine was 90 μM, CSF glycine 35 μM, with a CSF to plasma ratio of 0.39. Imaging by CT scan revealed massively dilated ventricles, and a significant increase in size of the posterior fossa cyst, compatible with a Dandy Walker malformation. A ventriculoperitoneal shunt was placed. During the following years, head circumference stabilized and progressively decreased to below the 3rd percentile at age 5 years. At 1 year of life, MRI revealed nearly complete absence of myelination in addition to the previously described CT abnormalities. These abnormalities persisted on follow-up. At age 51/2 years, he was profoundly retarded, functioning at a developmental level of three months, with social interactive skills at the 6 month level. Plasma glycine levels have always been in the 100 to 200 μM range. He has required multiple anticonvulsants.

Case 3.

This baby developed seizures and lethargy on the first day of life. Laboratory results included a plasma glycine level of 772 μM, a CSF glycine level of 167 μM, with a CSF to plasma glycine ratio of 0.21. Urine organic acids were normal. Lymphoblast glycine cleavage enzyme activity was absent. She was treated with 8.4 mg/kg of dextromethorphan per day and up to 480 mg/kg of sodium benzoate per day. Plasma glycine levels were 500 to 550 μM. She did not progress developmentally. At age 51/2 months, the head size had increased from the 25th percentile over two months to the 95th percentile. Brain MRI showed ventriculomegaly affecting all ventricles with transependymal transit of fluid, and loss of gyral and sulcal markings. There was a large retrocerebellar posterior fossa cyst. The corpus callosum was present but extremely thin. A ventriculoperitoneal shunt was placed at age 81/2 months with decreased irritability and stabilization of the head circumference at the 75th to 90th percentile. Computed tomography revealed continued ventricular enlargement, more prominent gyral and sulcal markings, and a posterior fossa cyst. Long-term follow-up showed persistence of ventriculomegaly. At age 41/2 years, developmental outcome was poor. She smiled and occasionally laughed, but had little reaction to the environment. Although she was able to roll over, she had very poor head control and could not sit. Medications included diazepam, benzoate, and dextromethorphan.

Case 4.

This boy became jittery within minutes of birth followed by progressive lethargy proceeding to coma, requiring intubation on day two. Electroencephalogram revealed a burst suppression pattern. The CSF glycine was 247 μM, with a CSF to plasma ratio of 0.20, confirming the diagnosis of NKH. He has been treated with 4.8 mg/kg of dextromethorphan per day and 500 mg/kg of benzoate per day. At 1 month of age, a head CT revealed moderately large ventricles and a slightly prominent cisterna magna. Head circumference was at the 75th percentile. At 2 months of age, he showed obtundation, forced downward deviation of the eyes, a bulging fontanel, and increased head circumference to above the 98th percentile. A CT scan revealed massive enlargement of supratentorial ventricles, effacement of the sulci and cisterns, and a megacisterna magna. A ventriculoperitoneal shunt was placed. At 3 months, head circumference stabilized at the 98th percentile. He had no interaction with his environment. Seizures were well controlled. He was fed by gastrostomy due to severe aspiration.

Discussion.

In all four patients, acute hydrocephalus occurred between ages of 2 to 6 months, requiring urgent ventriculoperitoneal shunting. Hydrocephalus had not been reported previously in NKH. Hydrocephalus presented with increasing irritability, increased seizures, papilledema, and increasing head size to greater than the 95th percentile. It involved the supratentorial ventricles in two patients, and all four ventricles in two patients. There was no increase in extra axial spaces to suggest impaired resorption of CSF by the arachnoid granulations. All four patients had a large retrocerebellar cyst that had not been noted before the acute hydrocephalus. The association of the large posterior fossa cystic malformation with obstructive hydrocephalus suggests a decompensation of a preexisting developmental malformation. The temporal relationship of the development of hydrocephalus and enlargement of the posterior fossa cyst suggests a possibly causal relationship.

Thin or absent corpus callosum has been reported in NKH as early as the first week of life.3,4 Pathology has shown cystic myelinopathy and gliosis,6,7 a usual preservation of gray matter,7 and a loss of Purkinje cells and granular neurons in the cerebellum.8,9 Magnetic resonance studies have shown absent or delayed myelination, its degree unrelated to CSF glycine levels.3 In a few patients, gyral malformations or cerebellar hypoplasia were reported.4 In our patients, we did not see gyral malformations, but the corpus callosum was very thin to nearly absent, and myelination was strikingly delayed to absent in all. The mild ventricular dilatation on the third day of life in Patient 1 suggests abnormalities occur very early.

All four patients were severely affected with NKH, presenting neonatally and having a high CSF to plasma glycine ratio (>0.2). There were no other known predisposing factors for the development of hydrocephalus. The plasma level of glycine varied from very low (Patient 1) to elevated (Patients 2 and 3) without correlation with the development of hydrocephalus. Medications shared by our patients included sodium benzoate and dextromethorphan, in widely varying doses. None of these medications has been previously reported to be associated with hydrocephalus in human patients. Recently, a fetal neurotoxic effect of dextromethorphan was reported in avian embryos.10 It is possible, though unlikely, that an agent with potential fetal neurotoxicity such as dextromethorphan, may enhance the already present cerebellar atrophy8,9 and contribute to the development of the posterior fossa abnormalities.

Outcome was very poor in all patients. There was profound mental retardation at the most severe end of the spectrum seen in NKH. Even after shunting, the ventricles remained significantly enlarged despite there being no evidence of increased pressure. Myelination was nearly absent in these regions. Marked brain atrophy was previously only reported in patients more than 1 year of age, and never in such young infants.3 Our three older patients had severe visual impairment consistent with absent myelination of the optic radiation. In conclusion, these findings suggest that the development of acute hydrocephalus in patients with NKH is associated with a dismal prognosis.

Acknowledgments

Acknowledgment

The authors thank the many physicians sharing the care for these complex patients.

References

  1. ↵
    Hamosh A, Maher J, Bellus GA, Rasmussen SA, Johnston MV. Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 1998;132:709–713.
    OpenUrlCrossRefPubMed
  2. ↵
    Boneh A, Degani Y, Harari M. Prognostic clues and outcome of early treatment of nonketotic hyperglycinemia. Pediatr Neurol 1996;15:137–141.
    OpenUrlCrossRefPubMed
  3. ↵
    Press GA, Barshop BA, Haas RH, Nyhan WL, Glass RF, Hesselink JR. Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations. Am J Neuroradiol 1989;10:315–321.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    Dobyns WB. Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia. Neurology 1989;39:817–820.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Van Hove JLK, Kishnani P, Muenzer J, et al. Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia. Am J Med Genet 1995;59:444–453.
    OpenUrlCrossRefPubMed
  6. ↵
    Brun A, Borjeson M, Sjoblad S, Akesson H, Litwin E. Neonatal non-ketotic hyperglycinemia. A clinical, biochemical and neuropathological study including electronmicrocopic findings. Neuropädiatr 1979;10:195–205.
  7. ↵
    Trauner DA, Page T, Greco C, Sweetman L, Kulovich S, Nyhan WL. Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia. J Pediatr 1981;98:272–275.
    OpenUrlCrossRefPubMed
  8. ↵
    Agamanolis DP, Potter JL, Lundgren DW. Neonatal glycine encephalopathy: biochemical and neuropathologic findings. Pediatr Neurol 1993;9:140–143.
    OpenUrlPubMed
  9. ↵
    Shuman R, Leech RW, Scott CR. The neuropathology of the nonketotic and ketotic hyperglycinemias: three cases. Neurology 1978;28:139–146.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Andaloro VJ, Monaghan DT, Rosenquist TH. Dextromethorphan and other N-methyl-d-aspartate receptor antagonists are teratogenic in the avian embryo model. Pediatr Res 1998;43:1–7.
    OpenUrlPubMed

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