The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients' major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

Autosomal-recessive dopa-responsive dystonia (DRD) is a rare clinical disorder presenting as bradykinesia, dystonia, tremor and even severe encephalopathy, and caused by tyrosine hydroxylase deficiency (THD). We report a case of compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive DRD herein. A 16-month-old Chinese boy presented with symptoms of movement disorder and growth retardation in his infant period. The genetic test revealed compound heterozygous mutations in the TH gene at c.457C>T and c.698G>A, which are pathogenic of DRD. The patient was administrated low-dose levodopa. The treatment resulted in the substantial improvement of dystonia. His long-term neurological outcome need follow-up for years. Gene mutation analysis is helpful and necessary to diagnose DRD and has important guiding significance for the subsequent treatment.