A study of cerebrospinal fluid neurotransmitters assay in children with undiagnosed neurological diseases in Hong Kong

Abstract

BACKGROUND: Paediatric neurotransmitter diseases (PNDs) are a group of disorders with a wide clinical spectrum of presentations including neonatal seizures, unexplained movement disorders such as dystonia, rigidity or ataxia, eye abnormalities including oculogyric crises, convergence spasm, ptosis or other intermittent ocular movement abnormalities, and autonomic symptoms like sweating, temperature instability, hypoglycaemia and hypothermia. METHODS: From 2004 to 2009, 114 children, aged 2 days to 33 years, with undiagnosed neurological diseases underwent lumbar puncture. Patients had one or more of the following symptoms: movement disorders, mental retardation/cognitive decline, epilepsy and spasticity which might be suggestive of disorders of biopterin, catecholamine and serotonin metabolism or cerebral folate deficiency. Extensive workup was unrevealing which included neuroimaging, cytogenetic studies, preliminary blood and urine for metabolic investigations. From 2004 to 2007, cerebrospinal fluid (CSF) was sent to the Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Switzerland (Dr N Blau) for neurotransmitters assay. From 2007 onwards, the analysis was performed in the Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong. RESULTS: The presenting features of our cohort included various combination of clinical symptoms such as dystonia/rigidity, epilepsy which could be intractable, cognitive regression, global developmental delay/mental retardation, oculogyric crises, spasticity and hypotonia. Ten (8.8%) patients had abnormal neurotransmitters profile compatible with 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency (n=5), tyrosine hydroxylase (TH) deficiency (n=2), idiopathic cerebral folate deficiency (CFD; n=2), aromatic L-amino decarboxylase deficiency (AADC) deficiency (n=1). Ultimate diagnosis was confirmed by genetic study in all patients with PTPS deficiency, TH deficiency and AADC deficiency. Two patients with CFD showed elevated autoantibodies against folate receptor (FR) confirming the diagnosis. Treatment was commenced in all 10 patients. One patient with PTPS deficiency revealed complete resolution of a parkinsonism state after replacement with tetrahydrobiopterin and L-dopa/carbidopa with normal intelligence. Another patient with PTPS deficiency only showed normalisation of hyperphenylalaninaemia without obvious clinical improvement with still significant generalised dystonia and moderate mental retardation. The remaining three patients with PTPS deficiency showed no neurological signs but with mild learning problem. One patient with TH deficiency demonstrated marked improvement in her dystonia and oculogyric crises after treatment with L-dopa/carbidopa and significant developmental progress. Another patient with TH deficiency did not reveal definite improvement and developed drug-induced dyskinesia. The child with CFD showed no more regression in cognitive and motor functions after replacement with folinic acid. His younger brother, who was nearly asymptomatic except mild spasticity over both lower limbs, did not have further deterioration in neurological functions after treatment. The patient with AADC deficiency was just started on bromocriptine and vitamin B6 treatment. CONCLUSION: Paediatric neurotransmitter disease, a group of potentially treatable neurometabolic diseases, should be considered in any child with unexplained neurological symptoms including movement disorder, cognitive regression, oculogyric crises and spasticity. Early identification and treatment will improve morbidity and mortality.