Retrospective Study of Patients with Hyperphenylalaninemia- Experience from a Tertiary Care Center in Pakistan.

OBJECTIVE: To assess the clinical and biochemical features as well as outcome of hyperphenylalaninemia patients. Methods: The descriptive retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data from January 2013 to February 2017 of plasma amino acid analysed at the Biochemical Genetic Laboratory of patients with phenylalanine levels >120 umol/L. Medical charts of patients registered with the Metabolic Clinics were reviewed, while outside referrals were contacted by telephone to collect data on a pre-structured questionnaire. Data was analysed using SPSS 21. RESULTS: Of the 18 patients, 13(72%) were males. Overall median age was 606 days (interquartile range: 761) and median phenylalanine levels were 1280 (interquartile range: 935) umol/L. Phenylalanine hydroxylase deficiency was present in 5(28%) patients while 3(16.6%) had defects in the metabolism or regeneration of tetrahydrobiopterin. The most common clinical features was intellectual deficit and seizures 14(78%) each, followed by lighter hair colour 10(55.5%) and hypotonia 11(61%). High treatment cost was the leading reason for cessation of therapy in 7(39%) followed by refusal by patient's family 5(28%). CONCLUSIONS: Most hyperphenylalaninemia cases were diagnosed late when intellectual disability had already developed.

Monoamine neurotransmitters and movement disorders in children and adults.

Neurotransmitter disorders comprise a rapidly expanding phenotypically and genetically heterogeneous group. Most of these disorders start in infancy through to childhood, although some forms may arise in adolescence and adulthood, and have various presentations. They may be overlooked if the phenotype leads to misdiagnoses involving various combinations of developmental disorders, hypotonia and movement disorders (dystonia, hyperkinesia, parkinsonism) or other clinical manifestations, such as sleep alterations and mood disorders. Neurotransmitter metabolite levels in cerebrospinal fluid (CSF) may help us to analyze and better understand the metabolic cascade and changes in dopamine and serotonin synthesis, and also guide genetic testing. Indeed, it is important to recognize these disorders in their early stages as they can be greatly improved by drug treatments, and if clinical responses are insufficient, then other agents that may enhance neurotransmission, such as serotonergic drugs and tetrahydrobiopterin (BH4) supplementation, could be considered. Also, a precise genetic diagnosis should be established by gene panels for dystonia, SNP microarrays and whole-exome sequencing. The present brief survey aims to review the present state of the art for the most commonly described and rare disorders of dopamine and serotonin, as well as cofactor deficiencies and dysfunctions, with an overview of clinical features, diagnostic strategies and treatments. Moreover, although these are mainly disorders of infants and children, many may nevertheless reach adulthood; thus, their evolution and treatments should be well known not only by pediatricians, but by neurologists as well, as the latter may be in charge at the stage of diagnosis (rarely) and during the follow-up of these rare patients.

The Utility of CSF for the Diagnosis of Primary and Secondary Monoamine Neurotransmitter Deficiencies.

Biogenic amine defects constitute a complex and expanding group of neurotransmitter disorders affecting cognitive, motor and autonomic system development, mostly in the pediatric age. In recent years different enzymatic defects have been identified impairing the tetrahydrobiopterin cofactor pathway and/or biogenic amine synthesis, catabolism and transport, with subsequent new disease entities described. The lumbar puncture, with subsequent withdrawal of cerebrospinal fluid (CSF), remains a key step in the diagnostic procedure. Due to the specific nature of CSF, timing of analysis, sample collection and storage, technical issues of the analytic process are still crucial for the diagnosis and follow-up of patients. A progressive approach to the diagnosis of biogenic amine defects is presented, pointing out criticalities and difficulties concerning sample collection and results interpretation, especially due to the increasing reports of secondary neurotransmitter alterations that, at present, constitute a challenge.