Publication

Abstract : To the Editor: A six-year-old boy, born to a non-consanguineous couple, presented with motor-predominant delay followed by regression. After starting walking at 2 y of age, he lost all the acquired milestones, including sitting, walking, and speaking following a febrile illness. Despite regression, he could recognize his parents and understand simple things but was non-ambulatory for last 4 y. At the illness onset, there was history of diurnal variation which disappeared over next 3–4 mo. There was history of developmental delay and similar regression (at 1.5 y age) in his four-year-old sister (non-ambulatory). Examination revealed normocephaly, marked central hypotonia, drooling, and head tilt. Brain MRI, basic metabolic workup, and prolactin levels for both were normal. Considering a possibility of dopa-responsive dystonia (DRD)-plus, both were started on levodopa at 1 mg/kg/d, gradually increased to 5 mg/kg/d. There was dramatic improvement over the next 4 wk with attainment of independent walking and speaking. Whole exome sequencing failed to reveal any significant variant explaining the phenotype. Strong clinical suspicion of DRD-plus led to whole-exome re-analysis revealing a novel homozygous variation in TH (tyrosine hydroxylase) gene (c.308T>C, exon14). Sanger sequencing in the affected sibling revealed same homozygous variation while both parents had same variation in heterozygous state confirming the diagnosis of tyrosine hydroxylase deficiency. At one-year follow-up, both children continue to gain milestones on 5 mg/kg/d levodopa. DRD-plus refers to non-neurodegenerative disorders with dopa-responsive dystonia and additional features like infantile-onset, developmental delay, neuro-regression, oculogyric crisis, etc. [1, 2]. These include neurotransmitter disorders like TH and sepiapterin reductase deficiency, etc. [1, 2]. Diagnosis in DRD-plus is often delayed due to presence of severe hypotonia instead of dystonia in patients with prolonged history and disappearance or absence of diurnal variation in severe cases. Diurnal variation at the onset of illness might be a diagnostic clue. Other dopa-responsive disorders include DRD and DRD look-alike disorders such as juvenile parkinsonism [3]. This report highlights the importance of phenotype-based focused genetic evaluation.