Novel PANK2 mutation in a Chinese boy with PANK2-associated neurodegeneration

Abstract

Rationale:Pantothenate kinase-associated neurodegeneration (PKAN), also called Hallervorden–Spatz Syndrome (HSS), is a rare neurodegeneration with brain iron accumulation from pantothenate kinase 2 gene (PANK2) mutation characterized as extrapyramidal symptoms. However, few studies involving PKAN patients were reported in China. This study was conducted to identify the genetic mutations in a Chinese boy with PKAN, and to review all PANK2 mutations reported in Chinese cases with PKAN.Patient concern:We reported a 23-year-old Chinese boy with PKAN, exhibiting difficulty in writing and manipulation using right hand with slow progression for 12 years. He spoke with a severe stutter when he was 15 years old.Diagnosis:Considering results of magnetic resonance images, brain computed tomography and medical history, the case was suspected to be related to genetic factors.Interventions:Whole exome sequencing was arranged, and the mutations were identified in his parents’ genome.Outcomes:In the present study, whole exome sequencing revealed 2 novel mutations (c.1696C > G in exon 7 and c.1160_c.1161insG in exon3) of the PANK2 gene in the proband. c.1696C > G and c.1160_c.1161insG, respectively, were confirmed in his father and mother. We also reviewed 14 different PANK2 mutations, most of which were missense type in Chinese cases. Those mutations did not show apparent hotspots, but exon 3 and 4 were frequently involved.Lessons:Two novel compound heterozygous mutations were identified and considered to be pathogenic in PKAN patients. This review of the reports indicated that atypical PKAN is the more common phenotype in China and no apparent genotype-phenotype correlation was found.

Enlarged Area of Mesencephalic Iron Deposits in Adults Who Stutter

“…Indeed, a minority of PKAN patients present with speech fluency disorders, which can precede the onset of other motor symptoms ( Zhang et al, 2019 ; Natteru and Huang, 2020 ). By contrast, hypoechogenicity of the midbrain has been reported in restless-legs syndrome and taken as indicating reduced iron deposition ( Schmidauer et al, 2005 ).…”

Psychiatric symptoms in an adolescent reveal a novel compound heterozygous mutation of the PANK2 gene in the atypical PKAN syndrome

“…These features have been observed in atypical PKAN cases and PANK2 gene mutation with a frequency of 60–77, 33–80, 40–89, 80–89, 67–92, 12.5%, respectively (Zhou et al ., 2001; Pellecchia et al ., 2005; Schiessl-Weyer et al ., 2015; Tomić et al ., 2015; Lee et al ., 2016). Psychiatric symptoms of our patient such as self-injury, impulsive or aggressive behaviors, visual and auditory hallucinations, dysphoria and attention deficit-hyperactivity disorder are features described in some PKAN cases (Pellechya et al ., 2005; Tomic et al ., 2015; Lee et al ., 2016; Zhang et al ., 2019). The psychiatric and not psychiatric symptoms of our patient and previous atypical PKAN cases are summarized in Table 1.…”

“…The beginning of the atypical form occurs in the second decade. Progression is slow with independent ambulation for 15 years, frequently characterized by dysarthria, dystonia, parkinsonism, tremor, gait alterations, dysphagia, cognitive decline, convulsions, acanthocytosis (rarely), retinopathy and psychiatric symptoms (Pellecchia et al ., 2005; Han et al ., 2016; Lee et al ., 2016; Zhang et al ., 2019). Here, we describe the case of an adolescent with psychiatric symptoms of PKAN syndrome with a novel compound heterozygous mutation in the PANK2 gene.…”

Cerebral Iron Deposition in Neurodegeneration

“…In another cellular model using patient-derived iPSCs differentiated into glutamatergic neurons, alteration of calcium homeostasis with calcium phosphate aggregates in the mitochondrial compartment was shown in addition to two-fold increased cellular Fe levels [177,178]. Moreover, globus pallidus calcifications located in the T2 hyperintense region can be detected also at a macroscopic level by brain CT in almost 50% of the patients [177,[179][180][181]. PKAN-patient-derived fibroblasts under high environmental Fe condition eagerly accumulated Fe in comparison to control cells.…”