Neurotransmitter disorders are a group of heterogeneous conditions that comprise defects in synthesis, transport, receptor binding, and degradation of neurochemical messengers. These rare disorders range from mild intermittent dystonia to lethal encephalopathies. The natural history and clinical presentation remain far from established. The study was conducted between October 2015 and September 2024. This study aims to describe the spectrum of clinical presentation, laboratory, imaging features, and genetic profiles of children diagnosed with neurotransmitter disorders and to assess the treatment modalities and clinical outcomes in these children. Among 29 patients, the median age was 12 months, with a male predominance. Positive family history was noted in 9 cases. The most frequent presentation was global developmental delay (GDD), dystonia, and seizures with autonomic disturbances, with diurnal variation. Various subcategories of neurotransmitter disorders are aromatic L amino acid decarboxylase deficiency-7 cases, tyrosine hydroxylase deficiency-3 cases, dopamine transporter deficiency syndrome-1 case, vesicular monoamine transporter 2 deficiency (VMAT2)-2 cases, GTP cyclohydrolase type deficiency-1 case, 6-pyruvoyl-tetrahydropterin synthase deficiency-1 case, dihydropteridine reductase deficiency-3, sepiapterin reductase deficiency-1 case, glycine encephalopathy-1 case, FOLR1-related cerebral folate transport deficiency-3 cases, and succinic semialdehyde dehydrogenase deficiency-5 cases. Metabolic workups were normal in all cases, with elevated phenylalanine levels in tandem mass spectrometry (TMS) in 5 children. Neuroimaging and electroencephalogram (EEG) were abnormal in 7 and 5 children, respectively. Multi-pronged and early treatment ensured better outcomes in these children. The most common type of neurotransmitter disorder in our series was aromatic L-amino acid decarboxylase deficiency, with the most common presentation being global developmental delay and dystonia.

Dihydropteridine reductase (DHPR) deficiency is a disorder that prevents regeneration of tetrahydrobiopterin (BH4), causing hyperphenylalaninemia (HPA) and low levels of neurotransmitters, including dopamine. Due to low levels of dopamine, patients present with hyperprolactinemia. Treatment consists of a phenylalanine (Phe)-restricted diet, hydroxytryptophan and levodopa (L-Dopa) supplementation, leading to a rapid normalization of prolactin (PRL) levels. We report a case of a patient with DHPR deficiency presenting with new symptomatic hyperprolactinemia and amenorrhea in adolescence despite appropriate management. The prolactinoma was confirmed with pituitary magnetic resonance imaging. The patient was started on cabergoline with rapid normalization of PRL levels and resolution of symptoms, in keeping with previous reports. Cabergoline has a stronger affinity for the D2R receptor and longer half-life than L-Dopa, leading to lactotroph apoptosis, tumor shrinkage, and rapid and maintained normalization of PRL levels, with a better side-effect profile. Patients with DHPR deficiency need to be actively monitored for symptomatic hyperprolactinemia, as L-Dopa monotherapy is insufficient to suppress PRL secretion, leading to lactotroph hypertrophy and proliferation over time and development of prolactinomas in later life.

Dihydropteridine reductase deficiency (DHPRD) is a rare genetic disorder of tetrahydrobiopterin (BH4) regeneration, a cofactor for several enzymes, including phenylalanine hydroxylase. Due to hyperphenylalaninemia (HPA), patients can be detected by the newborn metabolic screening, when available. The most common symptoms of DHPRD may mimic cerebral palsy: developmental/cognitive impairment, hypotonia, peripheral hypertonia, dystonia, feeding difficulties, epilepsy, and microcephaly. The long-term neurodevelopmental outcome is strongly influenced by the early initiation of effective treatment. A 2-year-old boy, born in Guinea, was evaluated in our center with the diagnosis of "cerebral palsy". He was born after a prolonged labor, and had feeding difficulties and severe developmental delay. Examination revealed microcephaly, axial hypotonia, and dyskinetic movements without hypertension. No seizures or oculogyric crisis were reported. Brain MRI showed slight brain atrophy and hyperintensity T2/FLAIR in basal ganglia. The diagnosis of cerebral palsy was questioned, and further investigation was carried out. HPA raised the possibility of BH4 deficiency, supported by increased biopterin in urine, decreased neurotransmitters in CSF, and low DHPR enzyme activity. A variant (128_130del (p.(Val43del)) in apparent homozygosity was later detected in the QPDR gene. At 4 years old, he started L-dopa/carbidopa, oxitriptan, and a phenylalanine-restrictive diet with moderate clinical improvement. When the diagnosis of "cerebral palsy" is questionable, other etiologies should be investigated, particularly disorders that have specific disease-modifying treatment. In our patient, the atypical constellation of neurological signs, brain MRI findings, and the nonexistence of newborn metabolic screening in the country of origin supported additional investigation. The presence of HPA-associated dystonia was crucial to the investigation and was later confirmed as DHPRD. Unfortunately, at this stage, the reversibility of the neurological damage in response to treatment is doubtful.

Biogenic amine neurotransmitters metabolism is a multistep pathway with pterin and pyridoxal phosphate (vitamin B6) as cofactors. A defect in biogenic amine and cofactor metabolism and vesicular transporters result in a primary neurotransmitter disorders. These are a well-recognized groups of inherited disorders and often present with features overlapping with other neurological conditions. Their diagnosis is made by analysis of biogenic amine metabolites in cerebrospinal fluid (CSF) and other body fluids and respective enzyme assays. Many of these disorders are treatable and deficits can be reverted by timely intervention. CSF biogenic amine or cofactor metabolite analysis is one of the primary indicators of a neurotransmitter disorder. In this paper, 3 cases are reported-2 of cofactor deficiency and 1 with enzyme deficiency wherein biogenic amine estimation has assisted in diagnosis.